CA3181782A1 - Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same - Google Patents

Abstract

The present disclosure relates to ultra-pure forms, polymorphs, amorphous forms, and formulations of N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridazine-3-carboxamide, referred to herein as Compound A: The present disclosure also relates methods of manufacturing and purifying the same, as well as intermediates useful in the synthesis of Compound A. The ultra-pure forms, polymorphs, amorphous forms, and formulations of Compound A can be used as therapeutic agents for the treatment of various diseases and conditions such as cancer.

Description

METHODS OF MANUFACTURING A BIFUNCTIONAL COMPOUND, ULTRAPU RE
FORMS OF THE BIFUNCTIONAL COMPOUND, AND DOSAGE FORMS
COMPRISING THE SAME
RELATED APPLICATIONS
[0001] This application claims priority to, and the benefit of, U.S.
Provisional Application No.
63/022,475, filed May 9, 2020, U.S. Provisional Application No. 63/149,143, filed February 12, 2021, and U.S. Provisional Application No. 63/1.77,378, filed April 20, 2021.
These applications are incorporated herein by reference in their entireties for all purposes.
TECHNICAL FIELD

[0002] This application relates to a bifunctional compound that has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome system.
In particular, the application relates to a process for manufacturing the bifunctional compound.
The application further relates to crystalline forms, amorphous forms, ultrapure forms, and stable forms of the bifunctional compound. The application also relates to oral dosage forms (e.g., tablets) comprising the bifunctional compound and methods of making the same, along with methods of treating cancer (e.g., prostate cancer) comprising administering a therapeutically effective amount of a dosage form of the invention to a subject in need of such treatment.
STATEMENT REGARDING FEDERALLY FUNDED RESEARCH

[0003] This invention was made with government support under grant number 01 by the National Cancer Institute. The government has certain rights in the invention.
BACKGROUND
100041 Most small molecule drugs bind to enzymes or receptors in tight and well-defined pockets. In contrast, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces typically involved. E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination, and therefore are attractive therapeutic targets due to their specificity for certain protein substrates. The development of ligands of E3 ligases has proven

4 PCT/US2021/031091 challenging, in part because they must disrupt protein-protein interactions.
However, recent developments have provided specific ligands which bind to these ligases. For example, since the discovery of nutlins, the first small molecule E3 ligase inhibitors, additional compounds have been reported that target E3 ligases, though the field remains underdeveloped.

[0005] One E3 ligase with particular therapeutic potential is cereblon, a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, indicating its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC). This complex ubiquitinates several other proteins. Through a mechanism not yet been completely elucidated, cereblon ubquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10).
FGF8, in turn, regulates several developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB I. forms a complex with DDB2, which functions as a DNA damage-binding protein.

[0006] Thalidomide, which has been approved for the treatment of a number of immunological indications, has also been approved for the treatment of certain neoplastic diseases, including multiple myeloma. In addition, thalidomide and several of its analogs are currently under investigation for use in treating a variety of other types of cancer. While the precise mechanism of thalidomide's anti-tumor activity is still emerging, it is known to inhibit angiogenesis. Recent literature discussing the biology of the imides includes 1,u et al. Science 343, 305 (2014) and Kninke et al. Science 343, 301 (2014).

[0007] Significantly, thalidomide and its analogs, e.g. pomalidomide and lenalidomide, are known to bind cereblon, and to alter the specificity of the complex to induce the ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), which are transcription factors essential for multiple myeloma growth. Indeed, higher expression of cereblon has been linked to an increase in efficacy of imide drugs in the treatment of multiple myeloma.
100081 Androgen receptor (AR) belongs to a nuclear hormone receptor family that is activated by androgens, such as testosterone and dihydrotestosterone (Phannacol. Rev.
2006, 58(4), 782-97; Vitam. Horm. 1999, 55:309-52.). In the absence of androgens, AR is bound by Heat Shock Protein 90 (Hsp90) in the cytosol. When an androgen binds AR, its conformation changes to release AR. from Hsp90 and to expose the Nuclear Localization Signal (NLS).
The NLS enables AR to translocate into the nucleus where AR acts as a transcription factor to promote gene expression responsible for male sexual characteristics (Endocr. Rev. 1987,

8(1)1-28; Mol.
Endocrinol. 2002, 16(10), 2181-7). AR deficiency leads to Androgen Insensitivity Syndrome, formerly termed testicular feminization.
100091 While AR is responsible for development of male sexual characteristics, it is also a well-documented oncogene in certain cancers including prostate cancer (Endocr. Rev.
2004, 25(2), 276-308). A commonly measured target of AR activity is the secreted Prostate Specific Antigen (PSA) protein. The current treatment regimen for prostate cancer involves inhibiting the androgen-AR axis by either of two methods. The first approach relies on reduction of androgens, while the second aims to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12,823-824). Despite the development of effective targeted therapies, most patients develop resistance and the disease progresses. An alternative approach for the treatment of prostate cancer may involve eliminating the AR protein. Because AR is a critical driver of tumorigenesis in many forms of prostate cancer, its elimination could lead to a therapeutically beneficial response.
1001.01 The bifunctional compound made and used according to the present invention is Compound A having the molecular formula of C411143CIEN906, and with the following structural formula:

N

NC od,N N
1\r'' .00.
100111 Compound A is under development as a PROTAC protein degrader that targets AR for the potential treatment of men having metastatic, castration-resistant prostate cancer (mCRPC).
SUMMARY
100121 The present disclosure provides ultra-pure forms, crystalline forms, amorphous forms, and formulations of N-[(1r,40-4-(3-chloro-4-cyanophenoxy)cyclohexy11-644-([442-(2,6-dioxopiperidin-3-y1)-6-fluoro-1,3-dioxo-2,3-dihydro-IH-isoindol-5-ylipiperazi n-1 -yl}methyl)piperidin-1-yl]pyridazine-3-carboxamide, referred to herein as Compound A, and processes for manufacturing Compound A:
o a "--N
H HirN "re-NC
CI I
(Compound A).
100131 In one aspect, this application pertains to a method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Compound A. In one embodiment, the method further comprises the administration of an additional anti-cancer agent.
[0014] In one aspect, this disclosure provides a crystalline form of Compound A having a powder x-ray diffraction pattern comprising peaks at 7.6 0.2 20, 11.5 0.2' 20, and 17.6' 0.2' 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A. This crystalline form is designated as "Form 2."
[0015] In another aspect, this disclosure provides a crystalline form of Compound A having a powder x-ray diffraction pattern comprising peaks at 11.0 0.2' 20, 16.1"
0.2' 20, and 17.9 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A. This crystalline form is designated as "Form 4."
[0016] In another aspect, this disclosure provides processes for manufacturing Compound A, wherein the process comprises the reductive amination of N-((lr,40-4-(3-chloro-cyanophenoxy)cycl ohexyl)-6-(4-formyl pi peri din-1-yl)pyri dazi ne-3-carboxam i de (Intermediate 3) with 2-(2,6-di oxopiperi di n-3-y1)-5-IIuoro-6-(pi perazi n-1. -yl)i soi n dol n e-1,3-di one hydrochloride (Intermediate 5) and a reducing agent to provide Compound A:

Cr:;NNON N,N 0 N _A/1 N r 'r intermediate 3 intermediate 5 J
N., ,N4 N N N - 'N=
Compound A
=
100171 In another aspect, this disclosure provides an intermediate useful for the synthesis of Compound A which is 6-chloro-N-((1r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (Intermediate 4), CI N
'N
N

Intermediate 4 100181 In another aspect, this disclosure provides an ultrapure form of Compound A having a purity greater than about 95 w0/0 100191 In another aspect, this disclosure provides processes for manufacturing an amorphous form of Compound A wherein the process comprises the following steps:
(I) dissolving crystalline Compound A in a solvent to afford a solution of Compound A;
(2) introducing the solution of Compound A from step (I) into a spray dryer to create the amorphous form of Compound A; and (3) Drying the amorphous form of Compound A to remove residual solvent.

[0020] Alternative methods of preparing amorphous forms of Compound A may include lyophilization, hot-melt extrusion, milling, or high-shear mixing.
[0021] In another aspect, this disclosure provides an oral dosage form comprising one or more pharmaceutically acceptable excipients and Compound A, wherein the oral dosage form is selected from the group consisting of a tablet, a sachet, or a capsule.
[0022] In a preferred aspect, the oral dosage form comprises one or more pharmaceutically acceptable excipients and an ultrapure form of Compound A.
[0023] In another aspect, this disclosure provides processes of manufacturing a tablet Compound A comprising the following steps:
(1) blending a form of Compound A with at least one pharmaceutically acceptable excipient to create a powder;
(2) delumping the powder from step (I), adding at least one pharmaceutically acceptable excipient, and blending to create a first blend;
(3) granulating the blend from step (2) and passing the resultant powder through a screen to produce a plurality of granules;
(4) adding at least one pharmaceutically excipient to the at least one granule from step (3) and blending to produce a second blend; and (5) compressing the second blend from step (4) into one or more tablets.
[0024] In another aspect, this disclosure provides methods of treating cancer in a subject comprising administering to a subject in need of such treatment one or more unit dosage forms (e.g., tablets) of the present disclosure. In one embodiment, the method further comprises the administration of an additional anti-cancer agent.
[0025] The preceding general areas of utility are given by way of example only and are not intended to limit the scope of the present disclosure or appended claims.
Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be appreciated by one of ordinary skill in the art in light of the instant claims, description, and examples. For example, the various aspects and embodiments of the invention may be utilized in numerous combinations, all of which are expressly contemplated by the present description. These additional advantages, objects, and embodiments are expressly included within the scope of the present disclosure. The publications and other materials used herein to illuminate the background of the invention, and in particular cases, to provide additional details respecting the practice, are incorporated by reference.
[0026] Where applicable or not specifically disclaimed, any one of the embodiments described herein are contemplated to be able to combine with any other one or more embodiments, even though the embodiments are described under different aspects of the disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[00271 FIG. 1 is a Differential Scanning Calorimetry plot for Compound A.
[0028] FIG. 2 is a dynamic vapor solution (DVS) isotherm plot of Compound A
obtained on a laboratory batch of Compound A having the same powder x-ray diffraction pattern as in FIG. 3A.
[0029] FIG. 3A is a powder X-ray diffraction pattern of Form 2 of Compound A
and FIG. 3B is a table that includes the peak listings of the diffraction pattern in FIG. 3A.
[0030] FIG. 3C is a powder X-ray diffraction pattern of Form 4 of Compound A
and FIG. 3D is a table that includes the peak listings of the diffraction pattern in FIG. 3C.
[0031] FIG. 4 is a 'II NMR Spectrum of Compound A in deuterated dimethylsulfoxide (DMSO-d6).
[0032] FIG. 5 is a 13C NMR Spectrum of Compound A in deuterated dimethylsulfoxide (DMSO-d6).
[0033] FIG. 6 is a high resolution mass spectrum of Compound A. High resolution mass spectrometry (MS) analyses of Compound A were conducted with flow injection analysis using positive ion electrospray [high-resolution electrospray ionization mass spectrometry (HR-ESI)] on a Thermo Orbitrap MS in Fourier Transform mode.
[0034] FIG. 7 shows the major peaks resulting from MS/MS fragmentation of the 812.308 parent ion from the high resolution mass spectrum of Compound A and FIG. 8A and FIG.
8B are an ion map and corresponding table showing the further fragmentation of the observed MS/MS ions (MS3).
[0035] FIG. 9 is an infrared spectrum of Compound A obtained on a Bomem MB-102 FTIR
spectrometer equipped with a DuraSamplIR diamond ATR probe. Key features which lend further support to the structure for Compound A are bands at 2225 cm'', representing a nitrile stretch vibration, and five peaks between 1774 and 1594, which represent four imide carbonyl vibrations and an amide carbonyl stretch vibration.

[0036] FIG. 10 shows the size distribution, as determined by a sieve analysis, of the Tablets of Pure Spray-dried Compound A.
100371 FIG. 11 is a series of line graphs showing the dissolution of crystalline vs. amorphous Compound A API. API (1 mg/mL) is present in gastric conditions (pH = 2), which is 2X diluted with FaSSIF at 30 minutes to increase the pH to 6.5. (API = active pharmaceutical ingredient;
FaSSIF = fasted state simulated intestinal fluid.) 100381 FIG. 12 is a series of line graphs showing the non-sink dissolution of spray-dried amorphous Compound A produced at multiple scales. API (500 gg/mL) is present in gastric conditions (pH = 2), which is 2X Diluted with FaSSIF at 30 minutes to increase the pH to 6.5.
100391 FIG. 13 is a series of line graphs showing the dissolution of prototype tablets in 900 mL a 37 C 50 mM Na2HPO4 pH 6.5, 0.5% sodium lauryl sulfate both immediately after manufacture (t....0) and after 2 weeks storage at 50 C/75% RH Open. The dotted line represents accelerating the agitation from 75 to 250 RPM to simulate long-term dissolution. (N=2).
[0040] FIG. 14 is flow diagram of the manufacturing process of the amorphous Compound A
spray-dried intermediate product.
[0041] FIG. 15 is a flow diagram of the manufacturing process of Compound A
tablets.
[0042] FIG. 16A is a chromatogram of crude Compound A, as produced by the First-Generation synthesis. Column: Shim-pack XR-ODS, 2.2gm 3.0 x 50 mm. Mobile phase A:
Water/0.05%1'FA.
Mobile phase B: Acetonitrile/0.05%TFA. Flow rate: 1.2 mL/min. Column temperature 40 C.
Detector, UV 254nm. FIG. 16B is the solvent gradient used to obtain the chromatogram in FIG.
16A. FIG. 16C is a chromatograph of Compound A following purification by prep-HPLC, as produced by the First-Generation synthesis. Column: Shim-pack XR-ODS, 2.2gm 3.0 x 50 mm.
Mobile phase A: Water/0.05%TFA. Mobile phase B: Acetonitrile/0.05%TFA. Flow rate: 1.2 mL/min. Column temperature 40 C. Detector, UV 254nm. FIG. 16D is the solvent gradient used to obtain the chromatogram in FIG. 16C
[0043] FIG. 17A is a chromatogram of crude Compound A, as produced by the Second-Generation synthesis. Column: Atlantis T3, 3 gm, 4.6 x 150 mm. Mobile Phase A: 0.1% TFA
in Water. Mobile Phase B:0.05% TFA in 75:25 ACN/Me0H. Flow Rate: 1.0 mL/min. Column temperature 45 C.
Detector: 260nm. FIG. 17B is a chromatogram of purified Compound A, as produced by the second-generation synthesis. Column: Atlantis T3, 3 gm, 4.6 x 150 mm. Mobile Phase A: 0.1%
TFA in Water. Mobile Phase B:0.05% TFA in 75:25 ACN/Me0H. Flow Rate: 1.0 mL/min.

Column temperature 45 "C. Detector: 260nm. FIG. 17C is the solvent gradient used to obtain the chromatogram in FIG. 17A and FIG. 17B.
[0044] FIG. 18A is a chromatogram of crude Compound A, as produced by the third-generation synthesis. Column: Atlantis 13, 3p.m, 4.6 x 150 mm. Mobile Phase A: Water with 0.1% TFA.
Mobile Phase B: 75:25 AcetonitrileiMe011 with 0.05% TFA. Column Temperature:
45 'C.
Detection: 260 nm. FIG. 18B is the solvent gradient used to obtain the chromatogram in FIG. 18A.
[0045] FIG. 19 is the 41 NMR spectrum of Intermediate 4, as produced by the second-generation synthesis, in deuterated dimethylsulfoxide (DMSO-d6).
[0046] FIG. 20 is an 1-11-NMR spectrum of Intermediate 8, produced by the second-generation synthesis, in deuterated dimethylsulfoxide (DMSO-d6).
[0047] FIG. 21 is an 1-11-N1vIR spectrum of Intermediate 9, produced by the second-generation synthesis, in deuterated dimethylsulfoxide (DMSO-d6).
100481 FIG. 22 is an 1-11-NMR spectrum of Intermediate 5, produced by the second-generation synthesis, in deuterated dimethylsulfoxide (DMSO-d6).
[0049] FIG. 23 is an FILNMR spectrum of Intermediate 2, produced by the third-generation synthesis, in deuterated dimethylsulfoxide (DMSO-d6).
[0050] FIG. 24 is an 1-11-NMR spectrum of Intermediate 3, produced by the third-generation synthesis, in deuterated dimethylsulfoxide (DMSO-d6).
[0051] FIG. 25 is an 1-1'-NMR spectrum of Compound A, produced by the third-generation synthesis, in deuterated dimethylsulfoxide (DMSO-d6).
[0052] FIG. 26 is a chromatogram of purified Compound A, as produced by the fifth-generation synthesis.
[0053] FIG. 27 shows a dissolution comparison between 5, 10, 20 and 40% SDI
tablet formulations. The vertical line represents the point of an "infinity" spin, when the paddle speed increased from 75 to 250 RPM.
[0054] FIG. 28 shows a dissolution comparison between 5% and 20% SDI loaded tablet formulations (D1, D2, D3 and D4). The vertical line represents the point of an "infinity" spin, when the paddle speed increased from 75 to 250 RPM.
[0055] FIG. 29 shows dissolution comparison between D2, G1* and G2* tablet compositions (525 mg tablet). Normalized for variable assay to the 90 minute time point. The vertical line represents the point of an "infinity" spin when the paddle speed increased from 75 to 250 RPM.

9 [0056] FIG. 30A and FIG. 30B show a comparison of granule size between the granules (A) and the final blend (B) 100571 FIG. 31 shows a dissolution comparison between D2, and G2 pre-demo tablets compressed at 2.0 and 2.5 MPa tensile strength (525 mg tablet). Normalized for variable assay to the 90 minute ti me point.
[0058] FIG. 32 shows a comparison of granule size between Compound A final blend demonstration batch for 20% API and pre-demo batch.
100591 FIG. 33 shows a dissolution comparison between 35 mg, 105 mg, and 140 mg demonstration batch tablets.
DETAILED DESCRIPTION
[0060] The present disclosure is related in certain aspects to US Patent Application Serial No.
1.5/730,728, issued as US Patent No. 10,584,101; US Patent Application Serial No. 16/577,901., issued as US Patent No. 10,844,021; and US Provisional Patent Application Serial Nos.
62/528,385 and 62/406,888. The present disclosure is related in certain aspects to US Patent Application Serial No. 17/075,808, now published as US 2021/0113557, and Provisional Patent Application Serial Nos. US 62/924,655, 62/945,418, 63/028,843, and 63/032,453.
Each of these applications are incorporated herein by reference in their entireties for all purposes.
DEFINITIONS
[0061] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is intended to describe particular embodiments only, and is not intended to limit the scope of the invention.
100621 Where a range of values is provided, it is understood that the range includes both of the endpoints with that range, as well as all intervening values.
[0063] The following terms are used to describe the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present invention.
100641 The articles "a" and "an" as used herein and in the appended claims are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, "an ultrapure form"
means one ultrapure form or more than one ultrapure form.
10065] The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both". Other elements may optionally be present other than the elements specifically identified by the "and/or" clause. Thus, as a non-limiting example, a reference to "A and/or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements).
[0066] As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."
[0067] In the claims, as well as in the specification, all transitional phrases such as "comprising,"
"including," "carrying," "having," "containing," "involving," "holding,"
"composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
[0068] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, means at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one"
refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B);
in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
1006911.1 should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise.
[0070] The terms "co-administration" and "co-administering" or "combination therapy" can refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time-varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time. In certain preferred aspects, one or more of the present compounds described herein, are co-administered in combination with at least one additional bioactive agent, especially including an anti-cancer agent. In particularly preferred aspects, the co-administration of compounds results in synergistic activity and/or therapy, such as, e.g., anti-cancer activity.
[0071] The term "effective" can mean, but is in no way limited to, that amount/dose of the active pharmaceutical ingredient, which, when used in the context of its intended use, effectuates or is sufficient to prevent, inhibit the occurrence, ameliorate, delay or treat (alleviate a symptom to some extent, preferably all) the symptoms of a condition, disorder or disease state in a subject in need of such treatment or receiving such treatment. The term "effective" subsumes all other effective amount or effective concentration terms, e.g., "effective amount/dose,"
"pharmaceutically effective amount/dose" or "therapeutically effective amount/dose," which are otherwise described or used in the present application.
[0072] The effective amount depends on the age, weight, gender, previous patient history or family history, type and severity of disease, the composition used, the route of administration, the stage of treatment, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. The exact amount can be ascertainable by one skilled in the art using known techniques in view of clinical data and medical experience (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams &
Wilkins).
[0073] The terms "pharmacological composition," "pharmaceutical composition,"
"therapeutic composition," "therapeutic formulation," and "pharmaceutically acceptable formulation" are known in the art.
[0074] The terms "pharmaceutically acceptable" and "pharmacologically acceptable" are known in the art.
[0075] The terms "pharmaceutically acceptable carrier" and "pharmacologically acceptable carrier" mean, but are not limited to, any and all solvents, excipients, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5%
human serum albumin.
Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art.
Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
[0076] The term "systemic administration" refers to a route of administration that is, e.g., enteral or parenteral, and leads to systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. For example, pharmacological compositions injected into the blood stream should be soluble. Other factors to avoid include toxicity, and any forms which prevent the composition or formulation from exerting its effect.
[0077] In one embodiment, Compound A may be solubilized in a vehicle suitable for parenteral administration by using a cyclodextrin. Exemplary cyclodextrins suitable for this process include, without limitation, sulfobetylether-P-cyclodextrin and (2-hydroxypropy1)-0-cyclodextrin.

[0078] Administration routes which lead to systemic absorption are known and include, without limitations: intravenous, subcutaneous, intra-peritoneal, inhalation, oral, buccal, sublingual, transdermal, intra-ocular, intra-nasal, intra-pulmonary, rectal, vaginal, and intra-muscular. The rate of entry of a drug into the circulation is a function of molecular weight or size. The use of a liposome or other drug canier comprising Compound A may potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A
liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages, may also be useful.
[0079] The term "local administration" refers to a route of administration in which the agent is delivered to a site that is proximal, e.g., within about 10 cm, to the site of the lesion or disease.
[0080] The formulation of the present invention preferably provides "oral administration" as used herein refers to enteral, buccal, sublabial, or sublingual medications in the form of tablets, capsules, syrups, powders, granules, pastilles, solutions, tinctures, elixirs, emulsions, hydrogels, teas, films, disintegrating tablets, mouthwashes, and others.
[0081] Suitable forms for oral administration may include one or more pharmaceutically acceptable excipients, including, for example, carriers, fillers, surfactants, diluents, sweeteners, disintegrants, binders, lubricants, glidants, colorants, flavors, stabilizing agents, coatings, or any mixtures thereof.
[0082] Carriers include, pharmaceutically acceptable excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
100831 Fillers include, but are not limited to, mannitol, sucrose, sorbitol, xylitol, microcrystalline cellulose, lactose, silicic acid, silicified microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, starch, pullulan and fast dissolving carbohydrates such as PharmaburstTM
fast disintegrating tablets, mixtures thereof, and the like. For examples of fast-dissolving carbohydrates see, e.g., U.S. Patent No. 8,617,588, which is incorporated herein by reference.
[0084] Surfactants include, but are not limited to, non-ionic, anionic, cationic, amphoteri.c or zwitterionic surfactants. Examples of suitable non-ionic surfactants include ethoxylated triglycerides; fatty alcohol ethoxylates; al kylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; Pluronics'A; alkyl polyglucosides; stearol ethoxylates; alkyl polyglycosi des.
Examples of suitable anionic surfactants include alkylether sulfates;
alkylether carboxylates; alkyl benzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates;
sarcosinates; alkyl sulfonates;
soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffin sulfonates; secondary n-alkarie sulfonates; alpha-olefin sulfonates; isethionate sulfonates. Examples of suitable cationic surfactants include fatty amine salts; fatty diamine salts; quaternary ammonium compounds;
phosphonium surfactants; sulfonium surfactants; sulfoxonium surfactants.
Examples of suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; amidobetaines.
Non-limiting examples of a surfactant that can be used in the ospemifene solid dispersions, include, for example.
Tween 20, Tween 80, Span 20, Span 80, sodium docusate (e.g., AOT), sodium lauryl sulfate, and poloxamers (e.g., poloxamer 407, Kolliphore EL, Pluronic F68). Poloxamers are also known by the trade names Synperonics , Pluronics , and Kolliphore/Cremophore.
[0085] Diluents include, but are not limited to, carbohydrates such as monosaccharides like glucose, oligosaccharides like sucrose and lactose (including anhydrous lactose and lactose monohydrate), starch such as maize starch, potato starch, rice starch and wheat starch, pregelatinized starch, calcium hydrogen phosphate, and sugar alcohols like sorbitol, mannitol, erythritol, and xylitol.
[0086] Sweeteners include, but are not limited to, sucrose, high fructose corn syrup, fructose, glucose, aspartame, acesulfame K, sucralose, cyclamate, sodium saccharin, neotame, rebaudioside A, and other stevia-based sweeteners.
[0087] Disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, chitosan, agar, alginic acid, calcium alginate, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkylsubstituted hydroxypropyl cellulose, hydroxylpropyl starch, low-substituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, magnesium aluminum silicate, polacrilin potassium, povidone, sodium starch glycolate, mixtures thereof, and the like.

[0088] Binders include, but are not limited to, hydroxypropylmethylcellulose (HP:MC), hydroxypropyl cellulose (HPC), povidone, copovidone (copolymers of vinylpyrrolidone with other vinyl derivatives), methylcellulose, powdered acacia, gelatin, gum arabicurn, guar gum, carbomer such as carbopol, and polymethacrylates.
[0089] Lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mixtures thereof, and the like.
[0090] Glidants include, but are not limited to, silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, mixtures thereof, and the like.
[0091] Flavors include, but are not limited to, menthol, peppermint oil, peppermint spirit, vanillin, and almond oil.
[0092] The term "Ubiquitin Ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 Ubiquitin Ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the covalent attachment of several ubiquitin molecules to an available lysine residue on a target protein, thereby targeting the protein for degradation by the proteasome. Thus, E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin conjugating enzyme, causes the transfer of ubiquitin to targeted proteins. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second; and a fourth is attached to the third. Such polyubiquitination marks the protein for degradation by the proteasome.
[0093] The terms "patient" and "subject" are used throughout this specification to referto an animal, preferably a mammal, more preferably a human or a domesticated or companion animal, to whom treatment, including prophylactic treatment, with a composition according to the present disclosure, is provided. For treatment of those conditions or disease states specific for a specific type of animal, such as a human patient, the term "patient" refers to that specific type of animal, including a domesticated or companion animal such as a dog or cat, or a farm animal such as a horse, cow, sheep, etc. In general, in the present disclosure, the term "patient" refers to a human patient unless otherwise stated or implied from the context of the use of the term.

[0094] "Pharmaceutically acceptable salt", as used herein with respect to a compound of the disclosure, means a salt form of that compound where the counterion is generally regarded as safe for therapeutic administration to a patient or subject, or otherwise presents an acceptable risk/benefit profile permitting therapeutic administration to a patient or subject. The term "pharmaceutically acceptable salt", as used herein with respect to a compound may also include solvates (e.g., hydrates) of such a salt, as well as cocrystals thereof.
[0095] Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromi de, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandel ate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsyl ate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.
[0096] "Solvate" means a solvent addition form of Compound A that contains either a stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with Compound A in which the water retains its molecular state as 1420, such combination being able to form one or more hydrates. In the hydrates, the water molecules are attached through secondary valencies by intermolecular forces, in particular hydrogen bridges. Solid hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalent with respect to their binding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally suitable are the hydrates of the pharmaceutically acceptable salts of Compound A.

[0097] Cocrystals represent novel forms of drug substances that would be suitable for incorporation in pharmaceutical solid dosage forms, and should enable formulation scientists to overcome a variety of problems that are encountered during development of traditional formulations. Cocrystals may be viewed as being an alternative to polymorphs, solvatomorphs, and salts, as cocrystals represent a different approach to solve problems related to dissolution, crystallinity, and hygroscopicity, among others. For further discussions of cocrystals, see:
Aitipaumula et al. "Polymorphs. Salts, and Cocrystals: What's in a Name?"
Crystal Growth Des.
2012, 12, 5, 2147-2152; and Brittain "Pharmaceutical Cocrystals: The Coming Wave of New Drug Substances" J. Pharrn. Sci. 2013, 102, 2, 311-317; both of which are incorporated by reference herein in their entireties.
[0098] The term "powder X-ray diffraction pattern", "PXRD pattern", "PXRD", "powder X-ray diffraction diagram", "X-ray diffraction pattern", or "XRPD" refers to the experimentally observed diffractogram or parameters derived therefrom. Powder X-ray diffraction patterns are characterized by peak position (abscissa) and peak. intensities (ordinate).
100991 The term "2 theta value" or "20" refers to the peak position in degrees based on the experimental setup of the X-ray diffraction experiment and is a common abscissa unit in diffraction patterns. The experimental setup requires that if a reflection is diffracted when the incoming beam forms an angle theta (0) with a certain lattice plane, the reflected beam is recorded at an angle 2 theta (20). The reference herein to specific 20 values for a specific solid form is intended to mean the 20 values (in degrees) as measured using the X-ray diffraction experimental conditions as described herein.
101001 "Isotopic derivative", as referred to herein, relates to Compound A
that is isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes. Thus, in one embodiment, Compound A is isotopically enriched or labelled with one or more atoms such as deuterium in place of one or more hydrogens.
[0101] Metastatic prostate cancer, or metastases, refer to prostate cancer that has spread beyond the prostate to other parts or organs in the body, e.g., bones, lymph nodes, liver, lungs, brain.
[0102] Castrate-resistant prostate cancer, or castration-resistant prostate cancer, (or prostate cancer that is castrate- or castration-resistant), is a type of prostate cancer that continues to grow even when the amount of testosterone in the body is reduced to very low levels.

[0103] Metastatic, castrate-resistant prostate cancer is a type of prostate cancer that has metastasized and continues to grow even when the amount of testosterone in the body is reduced to very low levels.
[0104] As used herein, "treating", "treatment", and the like, describe the administration of a pharmaceutical composition of the invention to a subject or patient for the purpose of combating a disease, condition, or disorder, which includes decreasing, mitigating or eliminating one or more symptoms or complications of the disease, condition or disorder, or decreasing, mitigating, or eliminating the disease, condition or disorder.
[0105] As used herein, "prevent", "preventing" and the like describe stopping the onset of the disease, condition or disorder, or one or more symptoms or complications thereof.
[0106] "Cmax", as used herein, refers to the observed maximum (peak) plasma concentration of a specified compound in the subject or patient after administration of a dose of that compound to the subject or patient.
[0107] "AUC", as used herein, refers to the total area under the plasma concentration-time curve, which is a measure of exposure to a compound of interest, and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng*H/mL (ng x H/mL), where "H" refers to hours.
[0108] "AUCiar", as used herein, refers to the AUC from 0 hours to the end of a dosing interval.
[0109] "AUC0-24" means the AUC from 0 hours to 24 hours after administration of a single dose.
[0110] "Controlled release" or "CR" as used herein with respect to an oral dosage form refers to a compound of the disclosure that is released from the dosage form, other than in an immediate release profile, according to a pre-determined profile that may include when and where release occurs after oral administration and/or a specified rate of release over a specified time period [0111] "Controlled release agent" as used herein with respect to an oral dosage form of the disclosure refers to one or more substances or materials that modify the release profile of a compound of the invention from the dosage form. Controlled release agents may be organic or inorganic, naturally occurring or synthetic, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid, colloidal silica, cellulosic derivatives, and combinations thereof.
[0112] "Enteric coating" as used herein with respect to a dosage form of the disclosure refers to a pH-dependent material that surrounds a core comprising a compound of the disclosure and which remains substantially intact in the acid environment of the stomach, but which subsequently dissolves in the pH environment of the intestines.
[0113] "Gastro-resistant" or "GR" as applied to a CR oral dosage form described herein means that release of a compound of the disclosure in the stomach of a subject shall not exceed 5%, 2.5%, 1% or 0.5% of the total amount of the compound of the disclosure in the dosage form.
[0114] "Loss on Drying" refers to the loss of weight expressed as percentage w/w/ resulting from water and volatile matter of any kind that can be driven off under specified conditions. Loss on Drying can be determined by persons of skill in the art using standard methods, including, for example, USP <731>.
[0115] The "Residue on Ignition" test (also known as the sulfated ash test) uses a procedure to measure the amount of residual substance not volatilized from a sample when the sample is ignited in the presence of sulfuric acid according to the procedure described below.
This test is usually used for determining the content of inorganic impurities in an organic substance. Residue on Ignition can be determined by persons of skill in the art using standard methods, including, for example, USP <281>.
[0116] "COA" stand for certificate of analysis.
[0117] "Oral dosage form" as used herein refers to a pharmaceutical drug product that contains a specified amount (dose) of a compound of the disclosure as the active ingredient, or a pharmaceutically acceptable salt and/or solvate thereof, and inactive components (excipients), formulated into a particular configuration that is suitable for oral administration, such as an oral tablet, liquid, or capsule. In one embodiment, the oral dosage form comprises a tablet. In one embodiment, the oral dosage form comprises a tablet that can be scored. In one embodiment, the oral dosage form comprises a sublingual tablet. In one embodiment, the oral dosage form comprises a capsule, which can be taken intact or used as a sprinkle onto food (e.g., applesauce or yogurt). In one embodiment, the oral dosage form comprises a sachet.
[0118] The term "about" and the like, as used herein, in association with numeric values or ranges, reflects the fact that there is a certain level of variation that is recognized and tolerated in the art due to practical and/or theoretical limitations. For example, minor variation is tolerated due to inherent variances in the manner in which certain devices operate and/or measurements are taken.
Thus, the term "about" is normally used to encompass values within standard error. In one embodiment, the term "about" as part of a quantitative expression such as "about X", includes any value that is up to 10% higher or lower than X, and also includes any numerical value that falls between X-10% and X+10% (e.g., X-5% and X+5%, or X-3% and X+3%). Thus, for example, a weight of about 40 g may include a weight of between 36 to 44 g, inclusive of the endpoints; a temperature of about 100 C may include a temperature of 90 C to 110 C, inclusive of endpoints;
and a temperature range of about 90¨ 1.00 C, may include a range o181 ¨ 110 C, inclusive of the endpoints. Thus, for example, a percent composition of about 50% may include a percent composition of between 45% to 55%, inclusive of the endpoints.
[0119] As used herein, "about 0 C" includes a temperature of -2 C to 2 C, inclusive of endpoints.
[0120] As used herein, the term "CDK inhibitor" refers to a compound that inhibits the enzymes in humans referred to as cyclin-dependent kinases (CDK). In one embodiment, the CDK inhibitor is a CDK4/6 inhibitor. As used herein, the term "CDK4/6 inhibitor" refers to a compound that inhibits CDK 4 and/or 6. Examples of a CDK inhibitor include, without limitation, SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or any pharmaceutically acceptable salt thereof In one embodiment, the CDK inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.
[0121] As used herein, the term "PARP inhibitor" refers to a compound that inhibits the enzymes in humans referred to as poly ADP ribose polymerase (PARP). Examples of a PARP
inhibitor include, without limitation, olaparib, nicaparib, talazoparib, niraparib, veliparib, pamiparib, CEP
9722, E7016, 3-aminobenzamide, mefuparib, and AZD2281.
[0122] "Comprising" or "comprises" as applied to a particular dosage form, composition, use, method or process described or claimed herein means that the dosage form, composition, use, method, or process includes all of the recited elements in a specific description or claim, but does not exclude other elements. "Consists essentially of' and "consisting essentially of' means that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not materially affect the recited physical, pharmacological, pharmacokinetic properties or therapeutic effects of the composition, dosage form, method, use, or process. "Consists of' and "consisting of' means the exclusion of more than trace elements of other ingredients and substantial method or process steps.
[0123] "Fasted condition" or "fasted state" as used to describe a subject means the subject has not eaten for at least 4 hours before a time point of interest, such as the time of administering Compound A. In an embodiment, a subject in the fasted state has not eaten for at least any of 6, 8, or 12 hours prior to administration of a compound of the disclosure.
[0124] "Fed condition" or "fed state" as used to describe a subject herein means the subject has eaten less than 4 hours before a time point of interest, such as the time of administering a compound of the disclosure. In an embodiment, a subject in the fed state has eaten within at least any of 3, 2, 1 or 0.5 hours prior to administration of a compound of the disclosure.
[0125] "Antacid medication", as used herein, refers to a substance that neutralizes stomach acidity in the subject. Antacids include, without limitation, bismuth subsalicylate, famotidine, and flavored liquids containing aluminum hydroxide and magnesium hydroxide (Maalox ). In one aspect, this application pertains to a subject who is administered Compound A, or a composition comprising Compound A, who is also taking, or being administered, an antacid medication.
[0126] All percentages provided herein are percentages by weight, and may be abbreviated wt%
or (w/w), unless indicated otherwise.
[0127] In one embodiment, the term "ultrapure", as used herein with reference to Compound A, refers to any of crystalline or amorphous forms of Compound A described herein that have a purity equal to or greater than about 95%, 96%, 97%, 98%, 99%, 99.5, or 99.9 wt%.
[0128] In one embodiment, the term "ultrapure", as used herein with reference to Compound A, refers to any of crystalline or amorphous forms of Compound A described herein that contains less than about 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of one or more impurities.
[0129] In one embodiment, the term "ultrapure", as used herein with reference to Compound A, refers to any of crystalline or amorphous forms of Compound A described herein that have a purity equal to or greater than about 95%, 96%, 97%, 98%, 99%, 99.5, or 99.9 wt%, and also contains less than about 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of one or more impurities.
[0130] As used herein, the term "impurity" refers to an unwanted compound, trace metal, or solvent that contaminates Compound A. In one embodiment, the impurity is a compound selected from the group consisting of Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4. In one embodiment, the impurity is a solvent that is selected from the group consisting of dichloromethane, methanol, and acetonitrile.

[0131] "Stable," as used herein with reference to Compound A, refers to forms of Compound A, including ultrapure forms, crystalline forms, ultrapure crystalline forms, amorphous forms, and ultrapure amorphous forms, that stably retain purity equal to, or greater than, 95%, 96%, 97%, 98%, 99%, 99.5, or 99.9% over a period of time (such as 6 months, 12 months, or 24 months) and under specified conditions (e.g., temperature and humidity) (such as 4 'C, 25 C, or 40 'C).
[0132] Compound A refers to the compound: N-[(1r,4r)-4-(3-chloro-4-cyan ophenoxy)cy cl ohexyl]-644-( 442-(2,6-di oxopiperi di n-3-yl)-6-fluoro- I
,3-di oxo-2,3-di hydro-IH-i soi ndo1-5-yl] pi perazi n-1-y1) m ethyl)pi peri di n-1 -ylipyri dazi ne-3-carboxam i de, that has a molecular formula of C41H43C1FN906, and has the following structural formula:

)NH

N N
(Compound A).
101331 Intermediate 1, as used herein, refers to the compound with the following structural formula:
Cl 0, , Intermediate 101341 Intermediate 2, as used herein, refers to the compound with the following structural formula:
N N
'N
H
=1,9 intermediate 2 [0135] Intermediate 3, as used herein, refers to the compound with the following structural formula:

0'7N----Th ..õs_r_N N,N
I N
1, Intermediate 3 [0136] Intermediate 4, as used herein, refers to the compound with the following structural formula:
CI N
,- NHr N
Intermediate 4 [0137] Intermediate 5, as used herein, refers to the compound with the following structural formula:

Ci 1,N.,,,..7.-j,c 7.----NH___0 Intermediate 5 101381 Intermediate 6, as used herein, refers to the compound with the following structural formula:
HO,,=0, N 0-)cs H
Intermediate 6 .
[0139] Intermediate 7, as used herein, refers to the compound with the following structural formula:

HCI
H2N,,a r.,..,N,õ,..,,;=
I
ib Intermediate 7 101401 Intermediate 8, as used herein, refers to the compound with the following structural formula:

F -s= ,>--- H
c Intermediate 8 101411 Intermediate 9, as used herein, refers to the compound with the following structural formula:
Boc intermediate 9 [0142] Intermediate 10, as used herein, refers to the compound with the following structural formula:

N,A
N` -.. OH
,....õ---..N)1õ,..:,,,-.-', Intermediate 10 101431 Impurity :I, as used herein, refers to the compound with the following structural formula.
OH
Cr)'µNCIN N
--- ' Ir\i N i .,, -,1,N,s, ,.N
."
0"0 0 CI
Impurity /
=

101441 Impurity 2, as used herein, refers to the compound with the following structural formula:
0 !I
N ...,') '''''.,-..--Jc )\¨N112 o NC -.)N
, H 'Y, N I Ci):1N o -..õ..-,..., r "N N- F -65-'--t C I -'..s'=
Impurity 2 [0145] Impurity 3, as used herein, refers to the compound with the following structural formula:
H
Q., õNI .0 0 I "sr '11 :
..." `= ==== ,i.t.,,, ..,"
r --r---str L l 0 0 rr'..-r'..
H
/I\
-y.t-.... sil r r ri- tsi' r =-="" \ ,.,.0- 1 0 ,,...-kk,...,A,0,. A.õ...........1 0 0.
Impurity 3 [0146] Impurity 4, as used herein, refers to the compound with the following structural formula:
...õ,-,\ ..."4:,,......-N, ,I, i " I Pa ...--.....,,, .... ri.,õ..õ....- 1,,,,,,...:N \ ....---..,), (....,:r F''''' .,:.:, 1 0 0 CO2Mt f.:se-1 \µ`.4" '0'. ''',-".
Impurity 4 COMPOUND A
The atoms in Compound A may be numbered as follows:

N 21 7 L........,...: 30 31 NH
, 15 i4N" *`= 17 -"'-- 28 , 36 " 38 41 9 s s I 22 26 0 NC 5 t 3 0 N 13 , N 2 r' s . r 3 1 F 35 33 32 ao 39 ..,. i 7 34 2 12 . ¨.. . . ..
101471 The centers carbon 10 and 7 are meso and by definition have no chirality and by definition are not stereogenic. The 1,4-trans relationship of the amide and ether on carbons 10 and 7, respectively, is supported by 11-1 nuclear magnetic resonance (NMR) in conjunction with 2-1) nOe NT.
[0148] Compound A has a stereogenic center at carbon 36 (denoted by an *
below). The starting materials for Compound A are sourced from racemic precursors, hence the molecule is racemic.
Thus, Compound A, in one embodiment, refers to a 50/50 mixture of enantiomers ¨ ent-1. and cm:-2 ¨ which have the following structures:

y¨NH
NC

. 6 ent-1 1, Ns NC' cr,,,, N N
N" -1\

ent-2 101491 As used herein, Compound A refers to a compound that is entirely ent-1, entirely ent-2, or any mixture of ent-1 and ent-2, including, for example a 50/50 (racemic) mixture of ent-1. and ent-2.
[0150] Compound A was originally disclosed in US Patent Application No.
15/730,728, which granted as US Patent No. 10,584,101 and which is incorporated by reference herein in its entirety.
MANUFACTURING PROCESSES OF ComPouND A
[0151] First Generation Process [0152] The first generation manufacturing process for Compound A was described in U.S. Patent No. 10,584,101, which is incorporated herein by reference. The process is summarized below in Scheme I and in the Examples section herein.
[0153] Scheme 1. First Generation Manufacturing Process of Compound A

F==,1 ------------------------- a ,.
------------------------------ HO ci. 0 .., --------------------------- 0 - ----------------------------NC
I +I N
Intermediate 6 Intermediate 1 H2N,, N N
'======= 'N
HCI = -Intermediate 7 N N N
-N H
H
N
N õ
Intermediate 2 Intermediate 3 H21tI'M 0 0 ci I
Intermediate 5 HN N, 0 N
d ci as.C7 Compound A
[0154] Second, Third, Fourth, and Fifth Generation Processes.
[0155] The second, third, fourth, and fifth generation processes are disclosed below and in the examples herein. These processes possess advantageous properties compared to the first generation synthesis. For example, the first generation process yielded Compound A with a purity of about 98 %. In contrast, later-generation processes yield Compound A with higher purity, e.g.
greater than 98%, greater than 99%, greater than 99.5%, etc.
[0156] Second Generation Process [0157] The second generation manufacturing process for Compound A is described below in Schemes 2-4 and in the Examples herein.

[0158] The synthesis used for the manufacture of Intermediate 4 is shown below in Scheme 2.
[0159] Scheme 2. Synthetic Process for the Manufacture of Intermediate 4.

0 Ac)<
CI CI intermediate HCI

Intermediate 7 Cl N
."0 01 CI
Intermediate 4 [0160] Step 1 involves an SnAr reaction between commercially-available 2,4-di ch I orobenzoni e and tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate in dimethylacetamide (DMA) with sodium hydride at 450 to afford intermediate 1.
The reaction is worked up with water and the precipitate dried to afford Intermediate 1. In the second step, the Boc protecting group is removed from Intermediate 1 by adding acetyl chloride in methanol at rt and the product is recrystallized in methyl tert-butyl ether to afford Intermediate 7. The third step involves amide coupling of Intermediate 7 and 6-chloropyridazine-3-carboxylic acid in ethyl acetate with triethylamine and propanephosphonic acid anhydride (T3P) to provide Intermediate 4. The reaction is quenched with 1 N aqueous I-ICI, and the crude Intermediate 4 is rinsed with ethyl acetate, filtered and dried. Intermediate 4 is added to isopropyl acetate and dimethylacetamide, filtered, and rinsed with IPAc.
[0161] The synthesis used for the manufacture of Intermediate 5 is shown below in Scheme 3.
[0162] Scheme 3. Synthetic Process for the Manufacture of intermediate 5.

FZ-1.....i.'0H --. ="),3:.\45-0 I ,N,...,... +
NH
,--= .0E-1 .
F 0';'-'s' N0 Boc H
intermediate 8 Boc'N , HA-Th 0 0 ' `-1 0 .....t.N1 _____________________ . N----< 0 -------1.

F-'-`=.µ"--------c(k h--: 1.\1 F
b d intermediate 9 Intermediate 5 [0163] In the first step, commercially-available 4,5-difluorophthalic acid and 3-aminopiperidine-2,6-dione are refluxed in acetic acid/acetate, and the reaction is quenched in water and the precipitate washed and dried to afford Intermediate 8. The second step involves an SnAr reaction between Intermediate 8 and commercially-available Boc-piperazine in N-methyl-2-pyrrolidone (NMP) with sodium bicarbonate at 900 to afford Intermediate 9. The reaction mixture is worked up with water/acetonitrile, filtered, washed with water, and dried to afford Intermediate 9. In the third step, the Bac protecting group is removed from Intermediate 9 with HC1 in methanol and methylene chloride. The reaction mixture is filtered and rinsed with methanol and methylene chloride to afford crude Intermediate 5 as a hydrochloride salt. Intermediate 5 is dissolved in water and dimethylacetamide, and recrystallized in isopropanol.

Scheme 4. Second Generation Manufacturing Process of Compound A
HO
CI,, N'N
N

:I 4. HNaõ..
CI OH
Intermediate 4 Intermediate 2 C".01 N 0 0 Li N Cr "LNH
40"0 11 CI
Intermediate 3 intermediate 5 N'Th 0 cNI0 , CI Os' Compound A
[0164] Step 1 in the process includes a SnAr reaction between Intermediate 4 and commercially available piperidin-4-y1 methanol in dimethylacetamide (DMA) with N,N-diisopropylethylamine at 90 ¨ 100 C to afford Intermediate 2. The reaction mixture is worked up with water and extracted with isopropylacetate (1PAc). The isopropylacetate layer is washed with water and concentrated to afford Intermediate 2 as an off white crystalline solid.
[0165] In some embodiments, Step 1 further comprises the step of purifying Intermediate 2 by recrystallization in an organic solvent. In some embodiments, the recrystallization further comprises the following steps:
i) combining crude Intermediate 2 in an organic solvent with an agent that promotes crystallization;
ii) reducing the volume of organic solvent;
iii) adding additional amounts of the organic solvent;
iv) stirring the mixture from part iii) at a temperature above 30 C for about 30 to about 60 minutes or longer;

v) cooling the mixture from part iii) to a temperature below 25 C over about 30 to about 60 minutes or longer;
vi) reducing the volume of organic solvent;
vii) stirring the mixture from part vi) at a temperature below 25 C, for about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, or about 120 minutes, or longer; and vii) filtering the mixture to obtain purified Intermediate 2.
[0166] In some embodiments, the organic solvent is isopropyl acetate. In some embodiments, the agent that promotes crystallization is a seed crystal of Intermediate 2. In some embodiments, the reducing of the volume of organic solvent in step ii) is performed by vacuum distillation. In some embodiments, the temperature of step iv) is about 50 C. In some embodiments, the temperature of step v) is about 20 C. In some embodiments, the temperature of step vii) is about 10 'C.
[0167] Step 2 is an oxidation of Intermediate 2 with 0.01 equivalents of TEMPO
(2,2,6,6-tetramethylpiperidin-1 -yl)oxyl and 1 equivalent of sodium hypochlorite (4.5 %
aqueous solution) solution in dichloromethane at <10 C to provide Intermediate 3. The reaction is quenched with 5% aqueous Na2S03 solution and the crude aldehyde product is extracted into dichloromethane.
The dichloromethane layer is di stillatively exchanged with acetonitrile.
[0168] In some embodiments, Step 2 further comprises the step of purifying Intermediate 3 by recrystallization. For example, in one embodiment, addition of water to the acetonitrile solution afforded Intermediate 3 as a white crystalline solid. In some embodiments, the recrystallization occurs in the presence of a solvent and an anti-solvent. In some embodiments, the recrystallization comprises the following steps:
i) combining crude Intermediate 3 with a mixture of solvent and anti-solvent;
ii) stirring the mixture of crude Intermediate 3, solvent, and anti-solvent;
and iii) filtering the mixture to obtain purified Intermediate 3.
[0169] In some embodiments, the solvent in i) is a polar aprotic organic solvent and the anti-solvent in i) is an aqueous solvent. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the anti-solvent is water. In some embodiments, the ratio of solvent to anti-solvent is about 1:1 (v/v). In some embodiments, the ratio of solvent to anti-solvent is about 1.04:1 (v/v). In some embodiments, step ii) is performed at a temperature between 15 C and 20 C. In some embodiments, step ii) is performed at a temperature of about 18 C. In some embodiments, step ii) is performed at a temperature of about 20 C. In some embodiments, the stirring of step ii) is performed for at least 12 hours, at least 14 hours, at least 16 hours, or at least 18 hours. In some embodiments, the stiffing of step ii) is performed for about 18 hours.
[0170] Step 3 is a reductive amination of Intermediate 3 with Intermediate 5 in dimethylacetamide with sodium triacetoxyborohydride (STAB) and triethylamine at 5 ¨ 10 C to afford Compound A. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is about 1.1:1. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is about 1.05:1. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is between about 1:1 and about 1.1:1. A mixture of ethanol and water is added to the crude reaction mixture and Compound A is precipitated as a yellow solid. Crude Compound A is dissolved in a mixture of dichloromethane:methanol (9:1). The product-rich solution is filtered and distillatively exchanged with ethanol. Crystallization from ethanol solution affords Compound A. as a light yellow crystalline solid which is dried in vacuo at 35 --- 45 C.
[0171] Third Generation Process [0172] The third generation manufacturing process for Compound A is described below in Scheme and in the Examples that follow.

Scheme 5. Third Generation Manufacturing Process of Compound A

i..) K , meo-u-i----,1 ______________________________________ HO' 0). .

...
-HO'AnA-OH
rQ't,01-1 N N'N'''"OH
E.):
-kr 'OH
1¨, 1¨, r:r0H

a I-IN OH
N
, Med,.. i HO
--sy -4 _____________________________________________ k arlea 1 NI 1 N
NJ IC _________________________ N
-, 14.' i Intermediate 10 1-õf4,..KPN
+
õ.. N
HO, õ;,,,,,, e.., I. ..-4..... -,.õ,,, .+Ncyk. ii, ._õ,;A:z.,2) Cj,,Nrit-o-K FI2N,,.r-L c-C
' He = ,,.. ...- a ,,, i Intermediate 2 iate Intermediate 7 Intermed intenned 1i ate 6 i..9 ...1 W

.6, Ci'Ts1 IV
y N
Iv Iv 1 40 II Cl , ,o-'",="' 'ci ,...
, c.7,,,,,r11:00,N--) 0 0 , Intermediate 3 Bo 1-1/1.Th ,y.:=,.; 1 ....,- s , a o Intermediate 8 Intermediate 9 Intermediate 5 , IV
n ..?
CP

F -e, JI, ,, Li C). : + r.',.(NH2 N
F, '''' ',./.r ;-1 0*'L''N '-0 H
1¨, Compound A

1¨, 101731 In the first step, the coupling of Intermediate 10 and Intermediate 7 in DMAc with DIPEA, ethyl cyan ohydroxyi mi noacetate, and 1-Ethy -3-(3-dimethylaminopropyl)carbodiimi de (EDCI) at about 40', followed by extraction with IPAc and water, and then rinsing the organic layer with IPAc and drying affords Intermediate 2.
101741 In some embodiments, the first step further comprises the step of purifying Intermediate 2 by recrystallization in an organic solvent. In some embodiments, the organic solvent is isopropyl acetate. In some embodiments, the recrystallization is performed by reduction of the volume of the organic solvent. In some embodiments, the reduction of the volume of the organic solvent is performed by vacuum distillation.
101751 Oxidation of Intermediate 2 with about 0.003 equivalents of TEMPO and about 1 equivalent of sodium hypochlorite (3.12 % aqueous solution) with sodium bicarbonate, sodium bromide, in dichloromethane and water at <5 C affords Intermediate 3.
The crude Intermediate 3 is extracted with dichloromethane and distillatively exchanged with acetonitrile. Addition of water to the acetonitrile solution afforded Intermediate 3 as a white crystalline solid. Reductive amination of Intermediate 3 with Intermediate 5 in dimethylacetamide with sodium triacetoxyborohydride (STAB) at 5 ¨ 10 C affords Compound A. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is about 1.1:1. A mixture of ethanol and water is added to the crude reaction mixture and crude Compound A is precipitated. Crude Compound A is dissolved in a mixture of dichloromethane:methanol (9:1). The product-rich solution is filtered and distillatively exchanged with ethanol. Crystallization from ethanol solution affords Compound A as a light yellow crystalline solid which is dried in vacuo at 25 C.
101761 In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of an alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of a secondary alcohol. In some embodiments, the oxidation of Intermediate 2 to afford intermediate 3 occurs in the presence of isopropanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-butanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-pentanol.
In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 3-methyl 2 butanol.
101771 In one embodiment, the second generation synthesis provides an ultrapure form of Compound A that has a purity of greater than about 95%. In certain embodiments, the ultrapure form of Compound A has a purity greater than about 96%, 97%, 98%, 99%, 99.5, or 99.9%.
101781 In one embodiment, the third generation synthesis provides an ultrapure form. of Compound A. that has a purity of greater than about 95%. In certain embodiments, the ultrapure form of Compound A has a purity greater than about 96%, 97%, 98%, 99%, 99.5, or 99.9%.
101791 Fourth Generation Process 101801 The fourth generation manufacturing process for Compound A is described below in Scheme 6 and in the Examples that follow.
Scheme 6. Fourth Generation Manufacturing Process of Compound A
N,, 0.NH2HCI p CI 0µµ ____________ 7r Intermediate 10 Intermediate 7 =
N õ 1;1 icr-- 1--=-=kx) crN
µ14 CI
= Cr Intermediate 2 interrnecliate 3 HCI-HN-Th P
0 Ls./Ai crNp, Intermediate 5 Compound A
101811 In the first step, the coupling of Intermediate 1.0 with excess Intermediate 7 in DMAc with DIPEA, catalyzed by 2-pyridinol 1-oxide (HOPO) and 1-Ethy1-3-(3-dimethylaminopropyl)carbodiimide (EDCI) at about 20 'V affords Intermediate 2.
In some embodiments, the molar ratio of Intermediate 10 to Intermediate 7 is about 1.00:1.05.

101.821 In some embodiments, the first step further comprises the step of purifying Intermediate 2 by recrystallization in an organic solvent. In some embodiments, the organic solvent is isopropyl acetate. In some embodiments, the recrystallization is performed by cooling the organic solvent. In some embodiments, the organic solvent is cooled to a temperature between about 15 C and about 25 'C. In some embodiments, the organic solvent is cooled to a temperature of about 20 'C.
101831 Oxidation of Intermediate 2 with about 0.01 equivalents of TEMPO and about 1 equivalent of sodium hypochlorite with sodium bicarbonate, sodium bromide, in dichloromethane and water at 0 C affords crude Intermediate 3. The crude Intermediate 3 was extracted with dichloromethane and distil latively exchanged with tetrahydrofiiran.
Addition of n-heptane to the tetrahydrofuran solution affords Intermediate 3 as a white crystalline solid.
101841 In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of an alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of a secondary alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of isopropanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-butanol. In some embodiments, the oxidation of Intermediate 2 to afford intermediate 3 occurs in the presence of 2-pentanol.
In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 3-methyl 2 butanol.
101851 Reductive amination of Intermediate 3 with Intermediate 5 in dimethylacetamide with sodium triacetoxyborohydride (STAB) and N-methylmorpholine at 0 C
affords Compound A. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is about 1.1:1. In some embodiments, the ratio of Intermediate 5 to N-methyl morpholine is between about 1.5:1 and about 2:1 (w/w). In some embodiments, the ratio of Intermediate to N-methyl morpholine is about 1.7:1 (w/w). A mixture of ethanol and water is added to the crude reaction mixture and Compound A is precipitated. Crude Compound A
is dissolved in a mixture of dichloromethane:methanol (17:1 w/w). The product-rich solution is filtered and distillatively exchanged with ethanol. Crystallization from ethanol solution affords Compound A as a light yellow crystalline solid which is dried in vacuo at 65 C.

101.861 in one embodiment, the fourth generation synthesis provides an ultrapure form of Compound A that has a purity of greater than about 95%. In certain embodiments, the ultrapure form of Compound A has a purity greater than about 96%, 97%, 98%, 99%, 99.5, or 99.9%.
101.871 Fifth Generation Process 101881 The fifth generation manufacturing process for Compound A follows the same general scheme as the fourth generation process described above.
101891 In the first step, the coupling of intermediate 10 with excess intermediate 7 in DMAc with DIPEA, catalyzed by 2-pyridinol 1-oxide (HOPO) and EDCI at about 20 C
affords Intermediate 2. In some embodiments, the molar ratio of Intermediate

10 to Intermediate 7 is about 1.00:1.02. In some embodiments, the precise amount of Intermediate 7 is adjusted based on the purity and potency of the Intermediate 7 used. In some embodiments, the precise amount of Intermediate 10 is adjusted based on the purity and potency of the Intermediate 10 used.
101901 In some embodiments, the first step further comprises the step of purifying Intermediate 2 by recrystallization in an organic solvent. In some embodiments, the organic solvent comprises tetrahydrofuran and n-heptane. In some embodiments, the organic solvent for the recrystallization of Intermediate 2 is seeded with crystals of pure Intermediate 2. In some embodiments, the recrystallization is performed by cooling the organic solvent. In some embodiments, the organic solvent is cooled to a temperature between about 15 C and about 25 'C. In some embodiments, the organic solvent is cooled to a temperature of about 20 C.
101911 Oxidation of Intermediate 2 with about 0.01 equivalents of TEMPO and about 1.15 equivalents of sodium hypochlorite with sodium bicarbonate, sodium chloride, and sodium bromide, in dichloromethane and water at 20 C affords Intermediate 3.
Addition of n-heptane and tetrahydrofuran to the solution affords Intermediate 3 as a white crystalline solid.
101.921 In some embodiments, the sodium hypochlorite is added to the reaction mixture rapidly. In some embodiments, the sodium hypochlorite is added over the course of less than 60 minutes, less than 45 minutes less than 30 minutes, or less than 20 minutes. In some embodiments, the sodium hypochlorite is added over the course of between about 15 and about 45 minutes. In some embodiments, the sodium hypochlorite is added over the course of about 30 minutes. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of an alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of a secondary alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of isopropanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-butanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-pentanol.
In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 3-methyl 2 butanol.
101931 Reductive amination of Intermediate 3 with Intermediate 5 in dimethylacetamide with sodium triacetoxyborohydride (STAB) and N-methylmorpholine at 0 C
affords Compound A. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is about 1.1:1. In some embodiments, the ratio of Intermediate 5 to N-methyl morpholine is between about 1.5:1 and 2:1 (w/w). In some embodiments, the ratio of Intermediate 5 to N-methyl morpholine is about 1.7:1 (w/w). A mixture of ethanol and water is added to the crude reaction mixture and Compound A precipitated. Crude Compound A was dissolved in a mixture of dichloromethane:methanol (17:1 w/w). The product-rich solution is filtered and distillatively exchanged with ethanol. Crystallization from ethanol solution affords Compound A as a light yellow crystalline solid which is dried in vacuo at 65 C.
101941 In the solvent swap from DCM into Et0H, auto-crystallization (self-seeding) occurs around a 1:1 ratio of DCM/Et0H content, which occurs shortly after 14 vol of Et0H
have been dispensed (end of atmospheric distillation; solvent swap 1). To have a more uniform and consistent filtration of mother liquors and washes, it is proposed to control the crystallization with seeding. Experiments showed that at reflux conditions, the product solution is supersaturated at/around 67% DCM content. In some embodiments, the seeding protocol comprises the following steps:
= Distill to supersaturation point (7 vol Et0H added) = Remove sample for DCM content to ensure DCM < 67%
(supersaturated) = Cool solution down to below reflux (-42 C) to 35 C

= Charge 0.5 wt% seed (based on Intermediate 3 input) at 35 "C
= Heat slurry back up to reflux and continue with remainder of solvent swap 10195) In one embodiment, the fifth generation synthesis provides an ultrapure form of Compound A that has a purity of greater than about 95%. In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, 97%, 98%, 99%, 99.5, or 99.9%.
101961 Purification of Compound A
101971 In one embodiment, the purification of Compound A comprises the following steps:
(1) dissolving Compound A in about a mixture of dichloromethane and methanol;
(2) filtering the solution comprising Compound A;
(3) distillatively exchanging the solvent of the solution comprising Compound A
with ethanol;
(4) crystallizing Compound A from the ethanol solution; and (5) drying the purified crystalline solid form of Compound A.
101.981 In one embodiment, the ratio of dichloromethane to methanol in (1) is about 9:1 (w/w). In one embodiment, the ratio of dichloromethane to methanol in (1) is about 10:1 (w/w) 10199) In one embodiment, the purification of Compound A comprises dissolving compound A in a solvent of between about 95:5 (w/w) and about 80:20 (w/w) mixture of dichloromethane and methanol.
102001 In one embodiment, the purification of Compound A comprises dissolving compound A in about an 80:20 (w/w) mixture of dichloromethane and methanol. In one embodiment, the purification of Compound A comprises dissolving compound A in about a 90:10 (w/w) mixture of dichloromethane and methanol. In one embodiment, the purification of Compound A comprises dissolving compound A in about a 95:5 (w/w) mixture of dichloromethane and methanol. In one embodiment, the purification of Compound A comprises dissolving compound A in about a 10:1 (v/v) mixture of dichloromethane and methanol.
102011 In one embodiment, the volume of ethanol in step (3) is between approximately 5 volumes and approximately 9 volumes relative to the amount of Intermediate 3 provided in the reductive amination step. In one embodiment, the volume of ethanol in step (3) is between approximately 6 volumes and approximately 8 volumes relative to the amount of Intermediate 3 provided in the reductive amination step. In one embodiment, the volume of ethanol in step (3) is approximately 7 volumes relative to the amount of Intermediate 3 provided in the reductive amination step.
102021 In some embodiments, the amount of ethanol in step (A3) is corrected for the ethanol content in the crude Compound A.
102031 In one embodiment, drying of the purified crystalline solid form of Compound A
is performed in vacuo. In some embodiments, the drying occurs at about 15 C
to about 30 C, about 20 C to about 30 C, about 30 C to about 40 C, or about 35 C to about 45 C.
En some embodiments, the drying occurs at greater than about 50 C, greater than about 60 C, greater than about 70 C, or greater than about 80 C. In some embodiments, the drying occurs at between about 60 C and about 70 C. In some embodiments, the drying occurs at about 65 C. In some embodiments, the drying occurs at between about 75 C
and about 85 C.
102041 In some embodiments, the drying occurs at about 80 C.
102051 Purification of Compound A
102061 In the following embodiments, the percent purity of Compound A, and the percent composition of one or more impurities, reflects the purity on a w/w basis.
102071 In some embodiments, the percent purity of Compound A, and the percent composition of one or more impurities, represents the purity as determined by HPLC (area %).
102081 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Intermediate 2.
102091 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Intermediate 2.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2.
102101 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Intermediate 2.
102111 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Intermediate 2.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2.
102121 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Intermediate 2.
102131 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A. has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Intermediate 2.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 2.
102141 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.1% of an impurity that is Intermediate 2.
[0215] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.1% of an impurity that is Intermediate 2.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2.
102161 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.05% of an impurity that is Intermediate 2.

102171 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.05% of an impurity that is Intermediate 2.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 2.
102181 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than 1% of an impurity that is Intermediate 3.
102191 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Intermediate 3.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 3.
102201 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Intermediate 3.

102211 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Intermediate 3.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an. impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 3.
102221 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Intermediate 3.
[0223] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than. about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Intermediate 3.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 3.

102241 in one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.1% of an impurity that is Intermediate 3.
[0225] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.1% of an impurity that is Intermediate 3.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 3.
[0226] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.05% of an impurity that is Intermediate 3.
102271 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.05% of an impurity that is Intermediate 3.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 3.
10228) In one embodiment, the ultrapure form of Compound A has a purity greater than 95%, and further comprises less than about 1% of an impurity that is Intermediate 5.
102291 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Intermediate 5.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 5.
102301 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Intermediate 5.
102311 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Intermediate 5.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is intermediate 5.In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Intermediate 5.
102321 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Intermediate 5.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 5.
102331 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.1% of an impurity that is Intermediate 5.
102341 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.1% of an impurity that is Intermediate 5.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 5.
102351 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.05% of an impurity that is Intermediate 5.
[0236] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.05% of an impurity that is Intermediate 5.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 5.
[0237] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Impurity I.
102381 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Impurity I. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about I%of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity I.
102391 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Impurity 1.
102401 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 1.In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Impurity 1.
102411 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96 A), and further comprises less than about 0.2% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 1.
102421 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.1% of an impurity that is Impurity 1.
[0243] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.1% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.1% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 1.
[0244] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.05% of an impurity that is Impurity 1.
102451 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.05% of an impurity that is Impurity 1.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.05% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.05% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.05% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.05% of an impurity that is Impurity 1.
Ihi one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.05% of an impurity that is Impurity I.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.05% of an impurity that is Impurity I.
102461 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Impurity 2.
102471 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1%of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is impurity 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 2.
102481 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Impurity 2.
102491 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Impurity 2.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 2.In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 2.1n one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Impurity 2.
[0250] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Impurity 2.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Impurity 2.
In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 2.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 2.
[0251] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.15% of an impurity that is Impurity 2.
102521 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.15% of an impurity that is Impurity 2.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.15% of an impurity that is Impurity 2.
In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 2.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 2.
102531 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Impurity 3.
102541 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1%of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 3, 102551 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Impurity 3.
102561 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Impurity 3.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 3.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 3.1r1 one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Impurity 3.
[0257] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Impurity 3.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Impurity 3.
In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 3.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 3.
[0258] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.15% of an impurity that is Impurity 3.
102591 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.15% of an impurity that is Impurity 3.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.15% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.15% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.15% of an impurity that is impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.15% of an impurity that is Impurity 3.
in one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 3.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 3.
102601 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Impurity 4.
102611 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1%of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 4, 102621 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Impurity 4.
102631 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Impurity 4.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 4.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Impurity 4.
[0264] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Impurity 4.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Impurity 4.
In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 4.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 4.
[0265] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.15% of an impurity that is Impurity 4.
102661 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.15% of an impurity that is Impurity 4.
In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.15% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.15% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.15% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.15% of an impurity that is Impurity 4.
in one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 4.
In one embodiment, the ultrapure form of Compound A has a purity of about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 4.
102671 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102681 In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5%
of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102691 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102701 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5%
of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102711 In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102721 In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5%
of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

102731 In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
[0274] In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5%
of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
[0275] In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
[0276] In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102771 In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5%
in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102781 In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5%
of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102791 In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102801 In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
102811 In one embodiment, the ultrapure forms of Compound A as described herein are crystalline.
[0282] In one embodiment, the ultrapure forms of Compound A as described herein are amorphous.
CRYSTALLINE FORMS OF COMPOUND A
102831 In one aspect, this application pertains to a crystalline form of Compound A
wherein Compound A is an ethanolate (i.e., an ethanol solvate). The XRPD
pattern corresponding to this crystalline form is referred to as Form 4, and is provided in FIG. 3C.
102841 The crystalline form of Compound A ethanolate, referred to as Form 4 and characterized by the XRPD pattern in FIG. 3C, has a powder x-ray diffraction pattern comprising at least one peak selected from the group consisting of 7.90 0.2"
20, 9.7 0.2 20, 11.00 0.2 20, 11.3 0.2 20, 13.60 0.2 20, 16.10 0.2 20, 17.2 0.20 20, 17.9 0.2 20 and 20.1 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A.
102851 In one embodiment, this crystalline form of Compound A ethanolate, i.e.
Form 4, has a powder x-ray diffraction pattern comprising peaks at 11.0 0.2 20, 16.1 0.2 20, and 17.9 0.2 20. In one embodiment, this crystalline form of Compound A
ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at

11.3 0.2 20. In one embodiment, this crystalline form of Compound A
ethanolate, i.e.
Form 4, has a powder x-ray diffraction pattern further comprising a peak at 17.2 0.2"
20. In one embodiment, this crystalline form of Compound A ethanolate, i.e.
Form 4, has a powder x-ray diffraction pattern further comprising a peak at 7.9" 4: 0.20 20. In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at 20.1' 0.2 20. In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at 13.6 0.20 20. In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at 9.7 0.2 20.

102861 In one embodiment, the crystalline form of Compound A ethanolate, i.e.
Form 4, has a powder x-ray diffraction pattern comprising peaks at 11.00 0.2 20, 11.3 0.2 20, 16.1 0.2 20, and 17.9 0.2" 20. In one embodiment, the crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern comprising peaks at 11.0 71: 0.2" 20, 11.3 . 0.2 20, 16.1 0.2 20, 17.2 71: 0.2 20, and 17.9 0.2' 20. In one embodiment, the crystalline form of Compound A ethanolate, i.e.
Form 4, has a powder x-ray diffraction pattern comprising peaks at 7.9 0.2 Mõ 11.0 * 0.2 20, 11.3 0.2 20, 16.1 0.2" 20, 17.2 0.2 20, and 17.9" 0.2 20. In one embodiment, the crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern comprising peaks at 7.9 0.2 20, 11.0 0.2 20, 11.3 0.2 20, 16.1 0.2 20, 17.2' 0.2 20, 17.9 0.2 20 and 20.1 0.2' 20. In one embodiment, the crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern comprising peaks at 7.9 0.2 20, 11.0 0.2 20, 11.3 0.2 20, 13.6 0.2 20, 16.1' 0.2 20, 17.2 0.2 20, 17.9" . 0.2 20 and 20.1 . 0.2" 20.
102871 In one embodiment, the crystalline form of Compound A ethanolate, i.e.
Form 4, has a powder x-ray diffraction pattern comprising peaks at 7.90 0.2 20, 9.7 0.2 20, 11.0 0.2 20, 11.3 0.2 20, 13.6 0.2" 20, 16.1 0.2 20, 17.2 0.2 20, 17.9"
0.2 20 and 20.1 0.2 20.
102881 In one aspect, this application pertains to a crystalline form of Compound A
characterized by the XRPD pattern in FIG. 3A, which is also referred to herein as Form 2.
102891 The crystalline form of Compound A., referred to as Form 2 and characterized by the XRPD pattern in FIG. 3A, has a powder x-ray diffraction pattern comprising at least one peak selected from the group consisting of 3.2 a': 0.2" 20, 7.6 :I-.
0.2" 20, 11.5' 71: 0.2' 20, 17.6 0.2 20, 18.5 0.2 20, and 21.4 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ku radiation at an x-ray wavelength of 1.5406 A.
In one embodiment, this crystalline form of Compound A, i.e. Form 2, comprises peaks at 17.5 , 7.6', and 11.5 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A. In one embodiment, this crystalline form of Compound A, i.e. Form 2, has a powder x-ray diffraction pattern further comprising a peak at 18.5" 0.2 20. In one embodiment, this crystalline form of Compound A, i.e. Form 2, has a powder x-ray diffraction pattern further comprising a peak at 21.4" 0.2" 20. In one embodiment, this crystalline form of Compound A, i.e. Form 2, has a powder x-ray diffraction pattern further comprising a peak at 3.2 0.2 20. In one embodiment, this crystalline form of Compound A, i.e. Form 2, comprises peaks at 7.6 0.2 20, 11.5 0.2 20, 17.6 0.2 20, and 18.5 0.2 20. In one embodiment, this crystalline form of Compound A., i.e. Form 2, comprises peaks at 7.6' 0.2 20, 11.5" 71:
0.2 20, 17.6 0.2' 20, 18.5 0.2 20, and 21.4 0.2 20. In one embodiment, this crystalline form of Compound A, i.e. Form 2, comprises peaks at 3.2 0.2 20, 7.6 0.2 20, 11.5 0.2 20, 17.6 0.2 20, 18.5' 0.2 20, and 21.4 0.2 20.
[0290] In one embodiment, the crystalline form of Compound A referred to as Form 2 and characterized by the XRPD pattern in FIG. 3A, serves as a convenient storage form for the preparation of the amorphous and/or ultrapure amorphous forms of Compound A
and further used in the preparation of pharmaceutical compositions of the disclosure, including, for example, tablets.
AMORPHOUS FORMS OF COMPOUND A AND THE MANUFACTURING PROCESS OF A SPRAY-DRIED INTERMEDIATE COMPRISING AN AMORPHOUS FORM OF COMPOUND A
102911 This application further provides an amorphous form of Compound A, or a salt or solvate thereof 102921 In one embodiment, the amorphous form of Compound A is ultrapure.
102931 In one embodiment, the amorphous form of Compound A is characterized by a glass transition temperature, Tg, of about 146 C at 25 C and 0% relative humidity.
[0294] In one embodiment, the amorphous form of Compound A is characterized by a glass transition temperature, Tg, of about 103 C at 40 C and 75% relative humidity.
102951 In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 0.1-10 gm.
102961 In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 0.5-8 gm.
102971 In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 0.6-7 gm.
102981 In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 0.7-6 }M.

102991 In one embodiment, the amorphous form of Compound A is characterized by a Dv( 10) particle size of about 0.8-5 gm.
103001 In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 0.5, 1, 2, 3, 4, 5, 6, 7, or 8 11111.
103011 In one embodiment, the amorphous form of Compound A is characterized by a Dv( 1 0) particle size of about 4 11111.
103021 In one embodiment, the amorphous form of Compound A is characterized by a Dv() 0) particle size of about 5 gm.
103031 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 5-15 gm.
103041 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 6-14 gm.
103051 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 7-13 gm.
103061 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 8-12 gm.
103071 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 9-11 gm.
103081 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 gm.
103091 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 9 gm.
103101 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 10 gm.
103111 In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 11 gm.
103121 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 5-25 gm.
103131 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 6-24 gm.

103141 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 7-23 gm.
103151 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 8-22 gm.
103161 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 9-21 gm.
103171 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 10-20 gm.
103181 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 gm.
103191 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 18 gm.
103201 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 19 gm.
103211 In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 20 gm.
103221 In some embodiments, the particle size of the amorphous form of Compound A is determined by laser diffraction.
103231 In one embodiment, the amorphous form of Compound A has a purity of greater than about 95%, 96%, 97%, 98%, 99%, 99.5, or 99.9%.
103241 In one embodiment, the amorphous form of Compound A is characterized in that the amorphous form is stable for at least 1 month at 2-8 C; for 1 month at 25 C and 60%
relative humidity; and for 1 month at 40 C and 75% relative humidity. In one embodiment, the amorphous form of Compound A is characterized in that the amorphous form is stable for at least 6 months at 2-8 C; for 6 months at 25 C and 60% relative humidity; and for 6 months at 40 C and 75% relative humidity. In one embodiment, the amorphous form of Compound A is characterized in that the amorphous form is stable for at least

12 months at 2-8 C; for 12 months at 25 C and 60% relative humidity; and for 12 months at 40 C and 75% relative humidity. In one embodiment, the amorphous form of Compound A is characterized in that the amorphous form is stable for at least 24 months at 2-8 C; for 24 months at 25 C and 60% relative humidity: and for 24 months at 40 C and 75%
relative humidity. In one embodiment, the stability of Compound A is assessed by storing it in wire-tied low-density polyethylene bags placed in heat-induction sealed, high-density polyethylene (HIRE) bottles containing a desiccant canister, and capped with a polypropylene-lined closure.
103251 This application also pertains to a method for manufacturing the amorphous form of Compound A, or a salt or solvate thereof. In one embodiment, the amorphous form of Compound A prepared according to the methods described herein is ultrapure.
[0326] In one embodiment, the amorphous form of Compound A is manufactured by taking an amount of Compound A, including any of the crystalline forms of Compound A, ultrapure forms of Compound A, and crystalline ultrapure forms of Compound A
described herein, and dissolving in an appropriate solvent until a clear solution is obtained. This solution of Compound A is introduced into a spray dryer and the damp solid output from the spray dryer is tray-dried to produce the amorphous solid form of Compound A, i.e., "the spray-dried intermediate." The spray-dried intermediate is checked for residual solvent before using in the preparation of pharmaceutical compositions comprising Compound A (e.g., tablets).
[0327] In one embodiment, the manufacturing process of an amorphous form of Compound A may be accomplished according to the flow diagram in FIG. 14.
103281 In one embodiment, the amorphous form of Compound A prepared as described above is useful in the preparation of pharmaceutical compositions, e.g., tablets, comprising Compound A.
[0329] In one embodiment, for the process of preparing the amorphous form of Compound A described herein, Compound A is dissolved in methanol, ethanol, isopropanol, 1-butanol, 2-butanol, acetone, tert-butyl methyl ether, diethyl ether, ethyl acetate, chloroform, dichloromethane, 2,2-dichlorethane, or any mixture thereof.
[0330] In one embodiment, for the process of preparing the amorphous form of Compound A described herein, Compound A is dissolved in a mixture of dichloromethane and methanol. In one embodiment, the mixture of dichloromethane and methanol is about 99/1 (w/w), about 95/5 (w/w). about 90/10 (w/w), about 85/15 (w/w), about 80/20 (w/w), about 70/30 (w/w), about 60/40 (w/w), about 50/50 (w/w), about 40/60 (w/w), about 30/70 (w/w), about 20/80 (w/w), about 10/90 (w/w), or about 1/99 (w/w). In a preferred embodiment, the mixture of dichloromethane and methanol is from about 70/30 (w/w) to about (w/w), preferably about 90/10 (w/w), and most preferably about 93/7 (w/w).
10331) In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A. in solvent to be introduced into the spray drier is from about 1 mg/mL to about 100 mg/mL.
103321 In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 1 mg/mL to about 50 mg/mL. In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 1 mg/mL to about 25 mg/mL. In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 1 mg/mL to about 10 mg/mL. In one embodiment, for the process of preparing the amorphous form of Compound A
described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 1 mg/mL to about 5 mg/mL. In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A
in solvent to be introduced into the spray drier is from about 2 mg/mL to about 5 mg/mL.
In one embodiment, for the process of preparing the amorphous form of Compound A
described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 2 mg/mL to about 4 mg/mL. In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 2 mg/mL to about 3 mg/mL.
103331 In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mLõ about 55 mg/mL, about 60 mg/mL, about 65 mg/mLõ about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 inglm L., about 90 mg/mL, about 95 mg/mL, or about 100 mg/mL.
103341 In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the amount of Compound A in solvent that is introduced into the spray drier is about 1 % (w/w), about 2 % (w/w), about 3 % (w/w), about 4 %
(w/w), about 5 % (w/w), about 6 % (w/w), about 7 % (w/w), about 8 % (w/w), about 9 %
(w/w), about 10 % (w/w), about 11 % (w/w), about 1.2 % (w/w), about 13 %
(w/w), about 14 % (w/w), or about 15 % (w/w). In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the amount of Compound A in solvent that is introduced into the spray drier is between about 1 and about 10 %
(w/w), between about 3 and about 8 % (w/w), between about 5 and about 7 % (w/w), between about 5.5 and about 6.8 % (w/w), or preferably between about 5.8 and about 6.2 % (w/w).
10335) In one embodiment, the process for manufacturing the amorphous form of Compound A comprises the following steps:
(1) dissolving crystalline and/or ultrapure Compound A in a solution of dichloromethane:methanol to afford a solution of Compound A;
(2) introducing the solution of Compound A from step (1) into a spray dryer;
(3) spraying the solution of Compound A from the spray dryer to create the amorphous form of Compound A; and (4) drying the amorphous form of Compound A to remove residual solvent.
103361 In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound A comprises dissolving Compound A in a solution of dichloroinethane and methanol of about 95:5 (w/w) to about 80:20 (w/w).
103371 In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound A comprises dissolving Compound A in an 80:20 (w/w) mixture of dichloromethane and methanol. In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound A comprises dissolving Compound A
in a 90:10 (w/w) mixture of dichloromethane and methanol. In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound A comprises dissolving Compound A in a 93:7 (w/w) mixture of dichloromethane and methanol. In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound A comprises dissolving Compound A in a 95:5 (w/w) mixture of dichloromethane and methanol.
103381 In one embodiment, the temperature of the solution in step (1) is about 20 C to about 40 C prior to introducing the solution into the spray dryer. In one embodiment, the temperature of the solution in step (1) is about 25 C to about 35 C prior to introducing the solution into the spray dryer. In one embodiment, the temperature of the solution in step (1) is about 27.5 C to about 32.5 C prior to introducing the solution into the spray dryer. In one embodiment, the temperature of the solution in step (1) is about 30 'C prior to introducing the solution into the spray dryer.
103391 The spray dryer used in the process for manufacturing the amorphous form of Compound A may be set at an appropriate temperature, gas flow rate, feed rated pressure as determined by one skilled in the art in view of this disclosure.
10340) In one embodiment, the spray dryer used in the process for manufacturing the amorphous form of Compound A has an SK80-16 nozzle and is employed using the following conditions:
Dryer Inlet Temperature: 65-125 C;
Dryer Outlet Temperature: 32.5-42.5 C;
System Gas Flow: 1550-2150 g/min;
Liquid Feed Rate: 145-205 g/min; and Liquid Feed Pressure: 300-600 psig.
103411 In one embodiment, the spray dryer used in the process for manufacturing the amorphous form of Compound A has an 5K80-16 nozzle and is employed using the following conditions:
Dryer Inlet Temperature: about 95 C;
Dryer Outlet Temperature: about 37.5 C;
System Gas Flow: about 1850 g/min;
Liquid Feed Rate: about 180 g/min; and Liquid Feed Pressure: about 450 psig.
103421 In one embodiment, the spray dryer used in the process for manufacturing the amorphous form of Compound A. has an Schlick Model 121 nozzle and is employed using the following conditions:

Dryer Inlet Temperature: 46-96 C;
Dryer Outlet Temperature: 30-40 C;
System Gas Flow: 60-100 kg/h;
Condenser Temperature: -10-0 C
Liquid Feed Rate: 3.5-8.5 kg/h; and Liquid Feed Pressure: about 50 bar.
103431 In one embodiment, the spray dryer used in the process for manufacturing the amorphous form of Compound A has an Schlick Model 121 nozzle and is employed using the following conditions:
Dryer Inlet Temperature: about 71 C;
Dryer Outlet Temperature: about 35 C;
System Gas Flow: about 80 kg/h;
Condenser Temperature: about -5 C
Liquid Feed Rate: about 6.0 kg/h; and Liquid Feed Pressure: about 50 bar.
103441 In one non-limiting embodiment, the amorphous form of Compound A is dried in step (4) by tray drying. In one embodiment, the amorphous form of Compound A
is dried in step (4) by filter drying. In one embodiment, the amorphous form of Compound A is dried in step (4) by tumble drying. In one embodiment, the amorphous form of Compound A is dried in step (4) by agitated conical drying. In one embodiment, the amorphous form of Compound A is dried in step (4) by fluid bed drying.
10345) In one non-limiting embodiment, the amorphous form of Compound A is tray-dried in step (4) to remove any residual solvent from the spray drying process.
103461 In one embodiment, the depth of the tray is about 2.5 cm.
103471 In one embodiment, the tray containing the amorphous Compound A is dried in step (4) for a total of 1, 2, 3,4, 5,6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, or 48 hours either under reduced or at ambient pressure.
In one embodiment, the tray containing the amorphous Compound A is dried for about 1 to about 24 hours. In one embodiment, the tray containing the amorphous Compound A is dried for about 1 to about 10 hours. In one embodiment, the tray containing the amorphous Compound A is dried for about 5 to about 10 hours. In one embodiment, the tray containing the amorphous Compound A is dried for about 5 to about 7 hours.
103481 In one embodiment, the temperature during the tray drying procedure in step (4) is ramped from about 20 C up to about 30 C, up to about 40 C, up to about 50 C, up to about 60 C, up to about 70 C, or higher.
103491 In one embodiment, the relative humidity during the tray drying procedure in step (4) is ramped up from about 15% relative humidity (RH) to about 20% RH, to about 25%
RH, to about 30% RH, to about 35% RH, to about 40% RH, to about 45% RH, to about 50% RH, or higher.
103501 In one embodiment, the tray-drying procedure in step (4) involves no ramping of either the temperature or the relative humidity, i.e., the temperature and relative humidity are held constant.
103511 In one embodiment, the tray-drying procedure in step (4) involves heating the product of step (3) in a bed depth of about 2.5 cm at about 40 C to about 60 C
for about 6 hours to about 18 hours at from about 5% RH to about 35% RH, under reduced or ambient pressure, where the temperature and relative humidity are both held constant.
103521 In one non-limiting embodiment, the amorphous form of Compound A is filter-dried to remove any residual solvent from the spray drying process.
103531 In one embodiment, the amorphous form of Compound A is filter-dried for a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, or 48 hours under vacuum. In one embodiment, the amorphous form of Compound A
is filter-dried for a total of from about 1 to about 50 hours. In one embodiment, the amorphous form of Compound A is filter-dried for a total of from about 12 to about 50 hours. In one embodiment, the amorphous form of Compound A is filter-dried for a total of from about 12 to about 36 hours. In one embodiment, the amorphous form of Compound A is filter-dried for a total of from about 20 to about 30 hours.
103541 In one embodiment, the pressure during the filter drying procedure is below ambient pressure. In one embodiment, the pressure during the filter drying procedure is about 0.1 bar, about 0.2 bar, about 0.3 bar, about 0.4 bar, about 0.5 bar, about 0.6 bar, about 0.7 bar, about 0.8 bar, or about 0.9 bar. In one embodiment, the pressure during the filter drying procedure is about 0.9 bar below ambient pressure.

103551 In one embodiment, the temperature during the filter drying procedure is ramped from about 20 C up to about 30 C, up to about 40 C, up to about 50 C, up to about 60 C, up to about 70 C, or higher.
MANUFACTURING PROCESS OF TABLET COMPRISING THE SPRAY-DRIED INTERMEDIATE
(I.E., THE UL1RAPURE AND STABLE AMORPHOUS FORM OF COMPOUND A) 103561 In one aspect, this application provides tablets comprising Compound A, and processes for manufacturing the same.
103571 In certain embodiment, the tablets of the disclosure comprise the amorphous form of Compound A, i.e., the spray-dried form disclosed herein. In one embodiment, the tablets of the disclosure comprise the amorphous form of Compound A that is also ultrapure. In one embodiment, the tablets contain about 2.5% to about 50% (w/w) of Compound A.
103581 Tablets of the disclosure may further comprise one or more pharmaceutically acceptable excipients, including, for example, carriers, fillers, surfactants, diluents, sweeteners, disintegrants, binders, lubricants, glidants, colorants, flavors, stabilizing agents, coatings, or any mixtures thereof.
103591 Fillers include, but are not limited to, mannitol, sorbitol, xylitol, microcrystalline cellulose, lactose, silicified microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan and fast dissolving carbohydrates such as PharmaburstTM, mixtures thereof, and the like. For examples of fast-dissolving carbohydrates, see U.S. Patent No. 8,617,588, which is incorporated herein by reference.
103601 Glidants include, but are not limited to, silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, mixtures thereof, and the like.
103611 Lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mixtures thereof, and the like.
103621 Disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, chitosan, agar, alginic acid, calcium alginate, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkylsubstituted hydroxypropyl cellulose, hydroxylpropyl starch, low-substituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, magnesium aluminum silicate, polacrilin potassium, povidone, sodium starch glycolate, mixtures thereof, and the like.
103631 In one embodiment, the tablets contain about 5% to about 95% w/w of one or more fillers, such as, e.g., about 75% to about 95% w/w, about 65% to about 85%
w/w, about 55% to about 75% w/w, about 45% to about 65% w/w, about 35% to about 55% w/w, about 25% to about 45% w/w, about 15% to about 35% w/w, or about 5% to about 25% w/w of one or more fillers.
103641 In one embodiment, the tablets contain about 80% w/w of one or more fillers.
103651 In one embodiment, the tablets contain about 1% to about 20% w/w disintegrant, such as, e.g., about 1% to about 15% w/w, about 1% to about 10% w/w, about 2%
to about 9% w/w, about 3% to about 8% w/w, about 4% to about 7% w/w, or about 5% to about 7%
w/w disintegrant.
103661 In one embodiment, the tablets contain about 0.20% to about 2.5% w/w lubricant, such as, e.g., about 0.2% to about 2.0% w/w, about 0.2% to about 1.8% w/w, about 0.2%
to about 1.5% w/w, or about 0.25% to about 1.5% w/w lubricant.
103671 In some embodiments, the tablets contain 0% to about 1% w/w glidant, such as, e.g., about 0.25% to about 0.75% w/w, or about 0.25% to about 0.50% w/w glidant.
103681 In one aspect, this application pertains to a process for manufacturing a tablet comprising Compound A.
[0369] In one embodiment, the process for manufacturing a tablet comprising Compound A comprises dry granulation. Dry granulation is a well-known pharmaceutical manufacturing process. In general, API is combined with appropriate excipients, including lubricant, and then compacted to form a mass. This mass typically is then comminuted or milled, then sieved to obtain the desired size of particle. Extragranular excipients are then added and mixed in, and the granular product is then compressed into tablets, filled into capsules or otherwise formed into a unitary dosage form in conventional fashion. In some embodiments, high dosage tablets comprising Compound A are produced by this process.

In other embodiments, the granular product comprising high dosage Compound A
is filled into capsules or otherwise formed into a unitary dosage form.
103701 In one embodiment, the process for manufacturing a tablet comprising Compound A comprises wet granulation. Wet granulation involves the formation of granules by the addition of a granulation liquid onto a powder bed of the API, which may be under the influence of an impeller, one or more screws, and/or air flow. After formation of the granules, the granulation liquid is removed by drying.
103711 In one embodiment, the process for manufacturing a tablet comprising Compound A comprises direct compression. In essence, direct compression bypasses the formation of a granule and involves the blending of an API with one or more pharmaceutically acceptable carriers, diluents, and/or other excipients, followed by compression.
103721 Compaction into a mass is accomplished using conventional equipment.
Typically, the blended API and excipients are passed through a roller compactor or a Chilsonator dry granulation roller/compactor apparatus for compaction. However, other means for compacting, e.g., compaction into slugs (or "slugging"), the API/excipient blend optionally are used. The compacted mass in turn is comminuted or milled, and then optionally sieved to produce the desired size granules.
103731 A dry granulated composition comprising Compound A is defined as the product of a dry granulation process. Dry granulated compositions include the direct product of dry granulation, i.e., dry granules per se, as well as products made from such granules including tablets, capsules, suppositories and other pharmaceutical dosage forms.
103741 In one aspect, this application pertains to a tablet comprising one or more pharmaceutically acceptable excipients and Compound A., including ultrapure forms of Compound A as described herein.
103751 In one embodiment, the tablet comprises from about 5 to about 1000 mg of Compound A. In one embodiment, the tablet comprises from about 5 to about 500 mg of Compound A. In one embodiment, the tablet comprises from about 5 to about 250 mg of Compound A. In one embodiment, the tablet comprises from about 25 to about 250 mg of Compound A. In one embodiment, the tablet comprises from about 25 to about 200 mg of Compound A. In one embodiment, the tablet comprises from about 25 to about 150 mg of Compound A. In one embodiment, the tablet comprises from about 5 to about 50 mg of Compound A. In one embodiment, the tablet comprises from about 30 to about 40 mg of Compound A. In one embodiment, the tablet comprises from about 65 to about 70 mg of Compound A. In one embodiment, the tablet comprises from about 100 to about 110 mg of Compound A. In one embodiment, the tablet comprises from about 135 to about mg of Compound A.
[0376] In one embodiment, the tablet comprises about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1.10, 115, 120, 125, 1.30, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of Compound A.
[0377] In one embodiment, the tablet comprises about 5 mg of Compound A.
[0378] In one embodiment, the tablet comprises about 35 mg of Compound A.
103791 In one embodiment, the tablet comprises about 70 mg of Compound A.
103801 In one embodiment, the tablet comprises about 105 mg of Compound A.
103811 In one embodiment, the tablet comprises about 140 mg of Compound A.
103821 In one embodiment, the tablet comprises about 175 mg of Compound A.
103831 In one embodiment, the tablet comprises about 200 mg of Compound A.
103841 In one embodiment, the tablet comprises about 210 mg of Compound A.
103851 In one embodiment, the tablet comprises about 245 mg of Compound A.
[0386] In one embodiment, the tablet comprises about 280 mg of Compound A.
[0387] In one embodiment, the tablet comprises about 315 mg of Compound A.
103881 In one embodiment, the tablet comprises about 350 mg of Compound A.
103891 In one embodiment, a tablet of the disclosure comprises about 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7. 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7. 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0,

13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5, or 50.0 % w/w of Compound A.
103901 In one embodiment, a tablet of the disclosure comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7. 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7. 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5, or 50.0 % w/w of an ultrapure form of Compound A.
10391) In one embodiment, a tablet of the disclosure comprises about 1 % to about 5 %
w/w of Compound A, about 2.5 % to about 7.5 % w/w of Compound A, about 10 % to about 15% w/w of Compound A, about 12.5 % to about 17.5 w/w of Compound A, about 15 % to about 20 % w/w of Compound A, about 17.5 % to about 22.5 % w/w of Compound A, about 20 % to about 25 % w/w of Compound A, about 22.5 % to about 27.5 % w/w of Compound A, about 25 % to about 30 % w/w of Compound A, about 27.5 %
to about 32.5 w/w of Compound A, or about 30 % to about 35 % w/w of Compound A.
In one embodiment, a tablet of the disclosure comprises about 1 % to about 5 %
w/w of an ultrapure form of Compound A, about 2.5 % to about 7.5 % w/w of an ultrapure form of Compound A, about 10 % to about 15 w/w of an ultrapure form of Compound A, about 12.5 % to about 17.5 % w/w of an ultrapure form of Compound A, about 15 % to about 20 % w/w of an ultrapure form of Compound A, about 17.5 % to about 22.5 % w/w of an ultrapure form of Compound A, about 20 % to about 25 % w/w of an ultrapure form of Compound A, about 22.5 % to about 27.5 % w/w of an ultrapure form of Compound A, about 25 % to about 30 % w/w of an ultrapure form of Compound A, about 27.5 % to about 32.5 % w/w of an ultrapure form of Compound A, or about 30 %
to about 35 % w/w of an ultrapure form of Compound A.
103921 In one embodiment, a tablet of the disclosure comprises:
about 2.5 % to about 7.5 % w/w of Compound A;

about 42 % to about 47 % w/w microcrystalline cellulose;
about 42 % to about 47 % w/w lactose monohydrate;
about 1 % to about 5 % w/w croscarmellose sodium;
about 0.1 % to about 1.0 % w/w silicon dioxide; and about 0.1. % to about 1.0 % w/w magnesium stearate.
103931 In one embodiment, a tablet of the disclosure comprises:
about 5% w/w of Compound A;
about 45.5 w/w microcrystalline cellulose;
about 45.5 % w/w lactose monohydrate;
about 3 % w/w croscarmellose sodium;
about 0.5 % w/w silicon dioxide; and about 0.5 % w/w magnesium stearate.
[0394] In one embodiment, a tablet of the disclosure comprises:
about 10 % w/w of Compound A;
about 57.3 % w/w microcrystalline cellulose;
about 28.7 % w/w lactose monohydrate;
about 3 % w/w croscarmellose sodium;
about 0.5 % w/w silicon dioxide; and about 0.5 % w/w magnesium stearate.
103951 In one embodiment, a tablet of the disclosure comprises:
about 20 % w/w of Compound A.;
about 50.7 % w/w microcrystalline cellulose;
about 25.3 % w/w lactose monohydrate;
about 3 % w/w croscarmellose sodium;
about 0.5 % w/w silicon dioxide; and about 0.5 % w/w magnesium stearate.
[0396] In one embodiment, a tablet of the disclosure comprises:
about 40 % w/w of Compound A;
about 37.3 % w/w microcrystalline cellulose;
about 18.7 % w/w lactose monohydrate;
about 3 % w/w croscarmellose sodium;

about 0.5 % w/w silicon dioxide; and about 0.5 % w/w magnesium stearate.
103971 In one embodiment, a tablet of the disclosure comprises:
about 2.5 % to about 7.5 w/w of an ultrapure form of Compound A;
about 42 % to about 47 % w/w microcrystalline cellulose;
about 42 % to about 47 % w/w lactose monohydrate;
about 1 % to about 5 % w/w croscarmellose sodium;
about 0.1 % to about 1.0 % w/w silicon dioxide; and about 0.1 % to about 1.0 % w/w magnesium stearate.
103981 In one embodiment, a tablet of the disclosure comprises:
about 5 w/w of an ultrapure form of Compound A;
about 45.5 % w/w microcrystalline cellulose;
about 45.5 % w/w lactose monohydrate;
about 3 % w/w croscarmellose sodium;
about 0.5 % w/w silicon dioxide; and about 0.5 % w/w magnesium stearate.
103991 In one embodiment, a tablet of the disclosure comprises:
about 10 % w/w of an ultrapure form of Compound A;
about 57.3 % w/w microcrystalline cellulose;
about 28.7 % w/w lactose monohydrate;
about 3 % w/w croscarmellose sodium;
about 0.5 % w/w silicon dioxide; and about 0.5 % w/w magnesium stearate.
1040011 in one embodiment, a tablet of the disclosure comprises:
about 20 % w/w of an ultrapure form of Compound A;
about 50.7 % w/w microcrystalline cellulose;
about 25.3 % w/w lactose monohydrate;
about 3 % w/w croscarmellose sodium;
about 0.5 % w/w silicon dioxide; and about 0.5 % w/w magnesium stearate.
104011 In one embodiment, a tablet of the disclosure comprises:

about 40 % w/w of an ultrapure form of Compound A;
about 37.3 % w/w microcrystalline cellulose;
about 1.8.7 % w/w lactose monohydrate;
about 3 % w/w croscarrnellose sodium;
about 0.5 % w/w silicon dioxide; and about 0.5 % w/w magnesium stearate.
104021 In some embodiments, a tablet of the disclosure comprises an intra-granular portion and an extra-granular portion. In some embodiments, the intra-granular portion comprises:
about 10 to about 40% w/w of Compound A;
about 35 to about 60% w/w microcrystalline cellulose;
about 15 to about 30% w/w lactose monohydrate;
about 1 to about 10% w/w croscarmellose sodium;
0 to about 1 % w/w silicon dioxide; and 0 to about 0.5% w/w magnesium stearate.
104031 In some embodiments, the intra-granular portion comprises:
about 10 to about 40% w/w of an ultrapure form of Compound A;
about 35 to about 60% w/w microcrystalline cellulose;
about 15 to about 30% w/w lactose monohydrate;
about 1 to about 10% w/w croscannellose sodium;
0 to about 1 % w/w silicon dioxide; and 0 to about 0.5% w/w magnesium stearate.
104041 In some embodiments, the extra-granular portion comprises:
about 1 to about 5% w/w croscannellose sodium;
0 to about 1 % w/w magnesium stearate; and 0 to about 2 % w/w silicon dioxide.
104051 In one embodiment, the tablet of the disclosure comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:
about 10 to about 40% w/w of Compound A;
about 35 to about 60% w/w microcrystalline cellulose;
about 15 to about 30% w/w lactose monohydrate;
about 1 to about 10% w/w croscannellose sodium;

0 to about 1 % w/w silicon dioxide; and 0 to about 0.5% w/w magnesium stearate;
and wherein the extra-granular portion comprises:
about 1 to about 5% w/w croscarmellose sodium;
0 to about 1 % w/w magnesium stearate; and 0 to about 2 % w/w silicon dioxide.
104061 In one embodiment, the tablet of the disclosure comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:
about 10 to about 40% w/w of an ultrapure form of Compound A;
about 35 to about 60% w/w microcrystalline cellulose;
about 15 to about 30% w/w lactose monohydrate;
about 1 to about 10% w/w croscarmellose sodium;
0 to about 1 % w/w silicon dioxide; and 0 to about 0.5% w/w magnesium stearate;
and wherein the extra-granular portion comprises:
about 1 to about 5% w/w croscarmel lose sodium;
0 to about 1 % w/w magnesium stearate; and 0 to about 2 % w/w silicon dioxide.
104071 In one embodiment, the tablet of the disclosure comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:
About 20% w/w of Compound A;
About 48.7% w/w microcrystalline cellulose;
About 24.3% w/w lactose monohydrate;
About 3% w/w croscarmellose sodium;
About 0.5 % w/w silicon dioxide; and About 0.25% w/w magnesium stearate;
and wherein the extra-granular portion comprises:
About 2% w/w croscarmellose sodium;
About 0.5% w/w magnesium stearate; and About 0.25 w/w silicon dioxide.

104081 in one embodiment, the tablet of the disclosure comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:
About 20% w/w of an ultrapure form of Compound A;
About 48.7% w/w microcrystalline cellulose;
About 24.3% w/w lactose monohydrate;
About 3% w/w croscarmellose sodium;
About 0.5 % w/w silicon dioxide; and About 0.25% w/w magnesium stearate;
and wherein the extra-granular portion comprises:
About 2% w/w croscarmellose sodium;
About 0.5% w/w magnesium stearate; and About 0.25 % w/w silicon dioxide.
10409) In some embodiments, the silicon dioxide in the extra-granular portion comprises fumed silica. Fumed silica (also known as pyrogenic silica) can be produced from compounds such as silicon chloride (SiCI4) by means of flame hydrolysis.
Suppliers of fumed silica include Evonik (Aerosile), Cabot Corporation (Cab-O-Sile), Wacker Chemie (HDK8), Dow Corning, Heraeus (Zandosi18), Tokuyama Corporation (Reolosile), OCI (Konasile), Orisil (Orisile) and Xunyuchem(XSILO). In some embodiments, the silicon dioxide in the extra-granular portion comprises fumed silica after treated with dimethyldichlorosilane. In some embodiments, the fumed silica comprises trimethylsilyl groups on the surface of the silica. In some embodiments, the silicon dioxide in the extra-granular portion comprises fumed silica chemically modified with trimethylsilyl groups on the surface of the silica.
104101 In one embodiment, the tablets of the disclosure are prepared according to the procedures in the Examples.
104111 In one embodiment, a dry granulation approach is used to produce Compound A
tablets as follows: the spray-dried intermediate, i.e., the amorphous form of Compound A, is blended with at least one pharmaceutically acceptable excipient to create a powder. In one embodiment, Compound A is blended with one or more fillers, one or more disintegrants, and one or more glidants. In one embodiment, Compound A is blended with two fillers, one disintegrant, and one glidant. In one embodiment, at least one filler is microcrystalline cellulose. In one embodiment, at least one filler is lactose monohydrade.
In one embodiment, the disintegrant is croscarmellose sodium. In one embodiment, the glidant is silicon dioxide. In one embodiment, Compound A is blended with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and silicon dioxide in a suitable blender.
104121 The resulting powder is delumped and a pharmaceutically acceptable excipient is added and blended. In one embodiment the pharmaceutically acceptable excipient is a lubricant. In one embodiment, the lubricant is magnesium stearate.
[0413] The blend is granulated using a suitable roller compactor and passed through a screen for appropriate sizing of granules.
104141 In one embodiment, granules prepared according to this process are about 400 gm to about 600 um in diameter.
[0415] In one embodiment, granules prepared according to this process are about 450 gm to about 550 gm in diameter.
104161 In one embodiment, granules prepared according to this process are about 575 gm to about 625 gm in diameter.
104171 In one embodiment, granules prepared according to this process are about 590 um to about 610 um in diameter.
104181 In one embodiment, granules prepared according to this process are about 595 gm to about 605 gm in diameter.
104191 In one embodiment, granules prepared according to this process are about 598 Am to about 602 um in diameter.
[0420] In one embodiment, granules prepared according to this process are about 450 gm in diameter, about 460 gm in diameter, about 470 gm in diameter, about 480 gm in diameter, about 490 gm in diameter, about 500 gm in diameter, about 510 um in diameter, about 520 gm in diameter, about 530 gm in diameter, about 540 gm in diameter, or about 550 gm in diameter.
104211 In one embodiment, granules prepared according to this process are about 500 gm in diameter.
104221 At least one pharmaceutically acceptable excipient is added and the bulk powder is blended in a suitable blender. In one embodiment, the pharmaceutically acceptable excipient is a lubricant. In one embodiment the lubricant is extragranular magnesium stearate.
104231 The blend is compressed into tablets and the resulting tablets packaged in bulk containers. In some embodiments, the blend is compressed into tablets using a rotary press.
104241 In one embodiment, the tablets of the disclosure are prepared according to the manufacturing process illustrated in the flow diagram in FIG. 15.
METHODS OF UBIQUITINATINGMEGRADING A TARGET PROTEIN IN A CELL
104251 The present disclosure further provides a method of ubiquitinatinWdegrading a target protein in a cell. The method comprises administering to a subject or patient in need thereof any of the forms of Compound A, or pharmaceutical compositions comprising any of these forms (e.g., tablets, capsules, parenteral solutions). Compound A
comprises an E3 ubiquitin ligase (cereblon) binding moiety and an androgen receptor (AR) targeting moiety linked through a linker moiety, such that ubiquitination of AR will occur when the target protein is placed in proximity to the ubiquitin ligase, thereby triggering proteasomal degradation to control or reduce protein levels of AR, and inhibiting the effects of AR.
METHODS OF TREATMENT
104261 In one embodiment, the present disclosure is directed to a method of treating a subject in need of treatment for prostate cancer modulated through AR where the ubiquitination and degradation of the AR protein results in a therapeutic effect in that subject, the method comprising administering to the subject a therapeutically effective amount of Compound A or any of the forms of Compound A disclosed herein, or compositions (e.g., tablets, capsules, parenteral solutions) of any of these forms. The disease state or condition may be causally related to the expression or overexpression of the AR protein.
104271 In one aspect, the present application pertains to a method of treating cancer.
104281 The methods of treating cancer described herein preferably result in a slowing or cessation of tumor growth, or more preferably a reduction in tumor size.
The cancer may be metastatic cancer, and this method of treatment may include inhibition of metastatic cancer cell invasion.
104291 In one embodiment, the cancer is prostate cancer.

104301 In one embodiment, the cancer is metastatic prostate cancer.
104311 In one embodiment, the cancer is castrate-resistant prostate cancer.
104321 In one embodiment, the cancer is metastatic, castrate-resistant prostate cancer.
104331 In one aspect, treating cancer results in a reduction in size of a tumor. A
reduction in size of a tumor may also be referred to as "tumor regression."
Preferably, after one or more treatments, tumor size is reduced by about 5% or greater, e.g., about 5 to about 40%, relative to its size prior to treatment; more preferably, tumor size is reduced by about 10% or greater, e.g., about 10% to about 50%; more preferably, reduced by about 20% or greater, e.g., about 20% to about 60%; more preferably, reduced by about 30%
or greater, e.g., about 30% to about 70%; more preferably, reduced by about 40% or greater, e.g, about 40% to about 80%; even more preferably, reduced by about 50% or greater, e.g., about 50% to about 90%; and most preferably, reduced by greater than about 75% or greater, e.g., about 75% to about 95%. Size of a tumor may be measured by any reproducible means of measurement. In a preferred aspect, size of a tumor may be measured as a diameter of the tumor.
104341 In another aspect, treating cancer results in a reduction in tumor volume.
Preferably, after treatment, tumor volume is reduced by about 5% or greater, e.g., about 5% to about 40%, relative to its volume prior to treatment; more preferably, tumor volume is reduced by about 10% or greater, e.g., about 10% to about 50%; more preferably, reduced by about 20% or greater, e.g., about 20% to about 60%; more preferably, reduced by about 30% or greater, e.g., about 30% to about 70%; more preferably, reduced by about 40% or greater, e.g., about 40% to about 80%; even more preferably, reduced by about 50% or greater, e.g., about 50% to about 90%; and most preferably, reduced by greater than about 75% or greater, e.g., about 75% to about 95%. Tumor volume may be measured by any reproducible means of measurement.
104351 In another aspect, treating cancer results in a decrease in number of tumors.
Preferably, after treatment, tumor number is reduced by about 5% or greater, e.g., about 5% to 40%, relative to number prior to treatment; more preferably, tumor number is reduced by about 10% or greater, e.g., about 10% to about 50%; more preferably, reduced by about 20% or greater, e.g., about 20% to about 60%; more preferably, reduced by about 30% or greater, e.g., about 30% to about 70%; more preferably, reduced by about 40% or greater, e.g., about 40% to about 80%; even more preferably, reduced by about 50% or greater, e.g., about 50% to about 90%; and most preferably, reduced by greater than about 75%, e.g., about 75% to about 95%. Number of tumors may be measured by any reproducible means of measurement. In a preferred aspect, number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is about 2x, 3x, 4x, 5x, 10x, or 50x.
104361 In another aspect, treating cancer results in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
Preferably, after treatment, the number of metastatic lesions is reduced by about 5% or greater, e.g., about 5% to about 40%, relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by about 10% or greater, e.g., about 10% to about 50%; more preferably, reduced by about 20% or greater, e.g., about 20 to about 60%; more preferably, reduced by about 30% or greater, e.g., about 30% to about 70%; more preferably, reduced by about 40% or greater, e.g., about 40% to about 80%; even more preferably, reduced by about 50% or greater, e.g., 50% to about 90%; and most preferably, reduced by greater than about 75%, e.g., about 75% to about 95%. The number of metastatic lesions may be measured by any reproducible means of measurement. In a preferred aspect, the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is about 2x, 3x, 4x, 5x, 10x, or 50x.
104371 In another aspect, treating cancer results in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone.
Preferably, the average survival time is increased by more than about 30 days;
more preferably, by more than about 60 days; more preferably, by more than about 90 days; and most preferably, by more than about 120 days. An increase in average survival time of a population may be measured by any reproducible means. In a preferred aspect, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation or completion of treatment with an active agent or compound of the disclosure. In another preferred aspect, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following a first round or completion of treatment with an active agent or compound of the disclosure.
104381 In another aspect, treating cancer results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
Preferably, the average survival time is increased by more than about 30 days;
more preferably, by more than about 60 days; more preferably, by more than about 90 days; and most preferably, by more than about 120 days. An increase in average survival time of a population may be measured by any reproducible means. In a preferred aspect, an increase in average survival time of a population may be measured by calculating for a population the average length of survival following initiation of treatment with an active agent or compound of the disclosure. In another preferred aspect, an increase in average survival time of a population may be measured by calculating for a population the average length of survival following completion of a first round of treatment with a compound of the disclosure.
104391 In another aspect, treating cancer results in a decrease in tumor growth rate.
Preferably, after treatment, tumor growth rate is reduced by at least about 5%, e.g., about 5% to about 40%, relative to growth rate prior to treatment; more preferably, tumor growth rate is reduced by at least about 10%, e.g., about 10% to about 50%; more preferably, reduced by at least about 20%, e.g., about 20% to about 60%; more preferably, reduced by at least about 30%, e.g., about 30% to about 70%; more preferably, reduced by at least about 40%, e.g., about 40% to about 80%; more preferably, reduced by at least about 50%, e.g., about 50% to about 90%; even more preferably, reduced by at least about 60%, e.g., about 60% to about 95%; and most preferably, reduced by at least about 75%, e.g., about 75% to about 99%. Tumor growth rate may be measured by any reproducible means of measurement. In a preferred aspect, tumor growth rate is measured according to a change in tumor diameter per unit time.
[0440] In another aspect, treating cancer results in a decrease in tumor regrowth.
Preferably, after treatment, tumor regrowth is less than about 5%; more preferably, tumor regrowth is less than about 10%; more preferably, less than about 20%; more preferably, less than about 30%; more preferably, less than about 40%; more preferably, less than about 50%; even more preferably, less than about 60%; and most preferably, less than about 75% Tumor regrowth may be measured by any reproducible means of measurement.
In a preferred aspect, tumor regrowth is measured by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. In another preferred aspect, a decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
104411 The dosages of the compound of the disclosure for any of the methods and uses described herein vary depending on the chemical agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
104421 The therapeutically effective amount of the compound of the disclosure may be administered one or more times over a day for up to about 30 or more days, followed by 1 or more days of non-administration of the compound. This type of treatment schedule, i.e., administration of a the compound of the disclosure on consecutive days followed by non-administration of the compound on consecutive days may be referred to as a treatment cycle. A treatment cycle may be repeated as many times as necessary to achieve the intended affect.
104431 In some embodiments, the method comprises administering to the subject a therapeutically effective amount of any of the forms of Compound A disclosed herein, or compositions of any of these forms in combination with at least one other bioactive agent.
In some embodiments, the at least one other bioactive agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is selected from a CDK inhibitor and a PARP
inhibitor. In some embodiments, the anti-cancer agent is a CDK inhibitor. In some embodiments, the anti-cancer agent is a CDK 4/6 inhibitor. In some embodiments, the anti-cancer agent is a PARP inhibitor. In some embodiments, the anti-cancer agent is selected from SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, pal bociclib, olaparib, rucaparib, talazoparib, niraparib, veliparib, pamiparib, CEP 9722, E7016, 3-aminobenzamide, mefuparib, and AZD2281. In some embodiments, the anti-cancer agent is selected from SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, and palbociclib. In some embodiments, the anti-cancer agent is selected from olaparib, rucaparib, talazoparib, niraparib, veliparib, pamiparib, CEP 9722, E7016, 3-aminobenzamide, mefuparib, and AZD2281. In some embodiments, the anti-cancer agent is selected from olaparib, rucaparib, talazoparib, and niraparib.
In some embodiments, the anti-cancer agent is olaparib.
EXAMPLES
104441 The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art in view of the present disclosure, without departing from the spirit of the present disclosure and/or scope of the appended claims.
Example 1. General Properties of Compound A
10445) The chemical and physical characteristics of Compound A are presented in Table 1. This batch was prepared for use in the 28-day good laboratory practice (GLP) toxicology studies using the same synthetic scheme and processing employed in preparation of active pharmaceutical ingredient (API) to be used in the clinical drug product.
10446) Table I. General Properties of Compound A
Physical Parameters Appearance Off-white to yellow powder Differential Scanning Calorimetry FIG. I (Endotherm at 289-300 C) Hygroscopicity by Dynamic Vapor FIG. 2 Sorption (DVS)' Powder X-ray Diffraction FIG. 3A
Powder X-ray Diffraction Peak Listing FIG. 3B
Optical Rotation (c=1, DMSO) 0 Solubility Parameters at 24 C 3 C
Solvent Conc. (mg/mL), 24 h Methanol 0.29 Acetonitrile 0.79 Dichloromethane 25.1 Dichloromethane/methanol 100 Ethanol 0.08 Ethyl acetate 0.20 Propylene glycol 0.75 Polyethylene glycol-300 2.8 pKa pKal = 6.8 pKa2 = 2.7 pH-Solubility Profile Buffer Concentration pH of solution (pg/mL) pH 1.2 HC1 (aq) 397 1.2 pH 3 200 mM citrate buffer 15 3.0 pH 5 200 mM citrate buffer 0.5 5.0 pH 6.5 200 mM citrate buffer 0.3 6.5 Fasted state simulated intestinal fluid 1 6.5 Fed state simulated intestinal fluid 22 5.0 The DVS was obtained on a laboratory batch having the same powder x-ray diffraction PXRD.
Example 2: First-Generation Synthesis of Cornpound A.
104471 Step 1: (tert-buty1N-1(1r,4r)-4-(3-ehloro-4-eyanophenoxy)cyclohexylkarbamate) (Intermediate 1). Into a 50.0-mL round-bottom flask, was placed tert-butyl N-Rir,40-4-hydroxycyclohexylicarbamate (500.0 mg, 2.32 mmol, 1.00 equiv), N,N-dimethylformamide (10.0 mi..), sodium hydride (82.8 mg, 3.45 mmol, 1.50 equiv), 2-chloro-4-fluorobenzonitrile (432.6 mg, 2.78 mmol, 1.20 equiv). The resulting solution was stirred for 2 hours at 0 C in a water/ice bath. The reaction was then quenched by the addition of 20.0 mL of water. The resulting solution was extracted with ethyl acetate (40.0 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (40.0 mL). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2). The collected fractions were combined and concentrated under vacuum. This resulted in 470.0 mg (58%) of Intermediate 1 (tert-butyl N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylicathamate) as yellow oil. LC-MS (ES): m/z 295.0 [MI-11], tR = 1.199 min, (1.90 minute run).
Chemical formula: C18H.23CIN203[350. 14].
10448) Step 2: (4-((('Jr,4r)-4-aminocyclohexyl)oxy)-2-chlorobenamitrile) (Intermediate 7) . Into a 50.0-mL round-bottom flask, was placed Intermediate 1 (tert-butyl N-R1r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamate) (470.0 mg, 1.34 mmol, 1.00 equiv), methanol (5.0 mL), hydrogen chloride. The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 340.0 mg (88%) of Intermediate 7 (2-chloro-4-[[(1r,40-4-aminocyclohexyl]oxy]benzonitrile) hydrochloride as a yellow solid. LC-MS (ES):
m/z 250.90 [Min, tR = 0.537 min, (1.90 minute run). Chemical formula:
C 131115CIN20[250.09].
104491 Step 3: (644-(hydroxymethyl)piperidin-l-yll-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylkyridazine-3-carboxamide) (Intermediate 2). Into a 100-ml, round-bottom flask, was placed 6-[4-(hydroxymethyl)pi peri di n-1-yl]pyridazi ne-3-carboxylic acid (1.0 g, 4.21 mmol, 1.00 equiv), Intermediate 7 (2-chloro-4-[(1r,40-4-aminocyclohexyl]oxybenzonitrile hydrochloride) (1.2 g, 4.18 mmol, 1.00 equiv), N,N-dimethylforrnamide (30 mL), N,N,N',N1-Tetramethy1-0-(7-azabenzotriazol-1-y1)uronium hexafluorophospate (2.4 g, 6.31 mmol, 1.50 equiv), N,N-diisopropylethylamine (1.6 g, 12.38 mmol, 3.00 equiv). The resulting solution was stirred for 1 hour at room temperature.
The reaction was then quenched by the addition of water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (v:v = 12:1). This resulted in 1.1 g (56%) of Intermediate 2 (644-(hydroxymethyl)piperidin-1-yli-N-R1r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide) as yellow oil. LC-MS (ES):
470.0 [MH+], IR = 0.90 min (1.8 minute run).
104501 Step 4: (6-(4-formylpiperidin-I-yI)-N-Wr,4r)-4-(3-chloro-4-cyanophenoxy) cyclohexy1.1 pyridazine-3-carboxamide) (Intermediate 3). Into a 100-mL round-bottom flask, was placed Intermediate 2 (700.0 mg, 1.49 mmol, 1.00 equiv), dichloromethane (20 mL), (1,1,1-Triacetoxy)-1,1-dihydro-1,2-benziodoxo1-3(1H)-one (947.2 mg, 2.23 mmol, 1.50 equiv). The resulting solution was stirred for 3 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (v: v = 1: 3). This resulted in 390.0 mg (56%) of Intermediate 3 as a yellow solid. LC-MS (ES'): /wiz 468.2 [MH1, tR =1.06 min (2.0 minute run).
104511 Step 5: (6-14-(14-12-(2,6-dioxopiperidin-3-y1)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindo1-5-ylipiperazin-.1-yllmethApiperidin-1-A-N-l(lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylkyridazine-3-carboxamide) (Compound A). Into a 100-mL
round-bottom flask, was placed Intermediate 3 (180.0 mg, 0.38 mmol, 1.00 equiv), dichloromethane (10 mL), Intermediate 5 (2-(2,6-di oxopiperidin-3-y1)-5-fluoro-(pi perazi n-1-y1)-2,3-di hydro-1H-i soi ndol e-1,3 -di one hydrochloride) (152.7 mg, 0.38 mmol, 1.00 equiv), sodium triacetoxyborohydride (244.6 mg, 3.00 equiv). The resulting solution was stirred for 3 hours at room temperature. The reaction was then quenched by water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (30 mL) and concentrated under reduced pressure. The solid was filtered out. HPLC analysis revealed the crude product to be 81.5% pure by area, with 16.9% by area identified as unreacted Intermediate 5. See FIG. 16A. The crude product was purified by Prep-HPLC with the following conditions: Column, )(Bridge Prep C18 OBD Column, 19*150mm 5 um;
mobile phase, water (10 mmol/L ammonium bicarbonate) and acetonitrile (48.0%
acetonitrile up to 73.0% in 8 min); Detector, IN 254nm. This resulted in 146.1 mg (47%) of Compound A. as a yellow solid. HPLC-UV analysis showed the purified product to be 98%
pure by area, with three impurities, quantified at 0.54%, 0.74% and 0.73%
respectively. See FIG.
16B 111. NMR (400 MHz, DMS0): 8 11.11 (s, 1}1), 8.58 (d, J = 8.2 Hz, 1}1), 7.86 (d, J =
8.8 Hz, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 11.4 Hz, 1H), 7.46 (d, J =
7.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 111), 7.34 (d, J = 9.7 Hz, 111), 7.15-7.12 (m, 1H), 5.13-5.08 (m, 1H), 4.59-4.45 (m, 3H), 3.90-3.83 (m, 1H), 3.27 (s, 4H), 3.03 (m, 2H), 2.97-2.82 (m, 1H), 2.64-2.53 (m, 511), 2.46(m, 1H), 2.23 (m, 2H), 2.14-2.09 (m, 211), 2.07-2.02 (m, 111), 1.96-1.79 (m, 5H), 1.65(m, 2H), 1..52(m, 211), 1.19-10.09(m, 2H); LC-MS (ES'): 812.25 [MH], tR = 1.57 min (3.0 minute run). Chemical Formula: C411143CIFN906 [811.30].
Total H count from 11NMR data: 43.

Example 3: Second Generation Synthesis of Compound A
104521 Step 1: N-((lr,40-4-63-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-('ydroxymethApiperidin-1-Apyridazine-3-carboxamide. To a clean, dry, 100-L
jacketed, glass reactor equipped with a temperature controller, two pen chart recorder, and a nitrogen bleed was charged dimethylacetamide (24 L, 5 vol), Intermediate 4 (4800.5 g, 1 wt), piperidin-4-y1 methanol (1699.9 g, 0.35 wt), and diisopropylethylamine (4759 g, 0.99 wt).
The temperature of the batch was adjusted to 90 C over 2 h, 7 min and the batch then held at 90 C for an additional 15 h. The reaction was monitored by HPLC. The temperature of the batch was adjusted to 50 C over 48 min then isopropyl acetate (48 L, 10 vol) added.
The batch was split into two equal portions (each 42 L) for work-up.
104531 Portion I Work-up. Portion 1 was charged to a clean, dry, 100-L, jacketed, glass reactor and heated to 50 C. Purified water (36 L, 7.5 vol) was charged and the batch stirred at 50 C for 5 min. The layers were allowed to separate and the lower aqueous layer was discarded to waste. Isopropyl acetate (12 L, 2.5 vol) and purified water (24 L, 5 vol) were charged and the batch temperature adjusted to 50 'C. The batch was stirred at 50 C
for 5 min, then the layers were allowed to separate, and the lower aqueous layer was discarded to waste. 1PC: NMR (TEST-2835) % DMAc 8.7% relative to Intermediate 2.
104541 Portion 2 Work-up. Portion 2 was charged to a clean, dry, 100-L, jacketed, glass reactor and heated to 50 C. Purified water (36 L, 7.5 vol) was charged and the batch stirred at 50 "C for 5 min. The layers were allowed to separate and the lower aqueous layer was discarded to waste. Isopropyl acetate (12 L, 2.5 vol) and purified water (24 L, 5 vol) were charged and the batch temperature adjusted to 50 C. The batch was stirred at 50 C
for 6 min, then the layers were allowed to separate, and the lower aqueous layer was discarded to waste. 1PC: IFINMR (TEST-2835) % DMAc 2.8% relative to Intermediate 2.
104551 The combined isopropyl acetate extracts were returned to the 100-L
reactor.
Intermediate 2 Seeds (48.82 g, 0.01 wt,) were charged and the batch temperature adjusted to 15 C over 2 h. The batch was distilled under vacuum (Jacket Temp. 35 C) until 26 L
(5.4 vol) remained. Isopropyl acetate (46 L, 9.6 vol) was added and the batch temperature adjusted to 50 C over 1 h. The batch was stirred at 50 C for 36 min then cooled to 20 C

over 28 min. The batch was distilled under vacuum (Jacket Temp. 35 C) until 28 L (5.8 vol) remained, then the temperature adjusted to 10 C over 18 min, and stirred at this temperature for 1 h, 18 min. The precipitated solid was isolated by vacuum filtration on a 24 inch, polyethylene filter funnel. The reactor was rinsed with isopropyl acetate (24 L, 5 vol) and the rinse used to wash the filter cake. The wet cake was further washed with isopropyl acetate (24 L, 5 vol). After conditioning on the filter under nitrogen for 46 min, the wet-cake was transferred to eight glass drying trays (wet weight 6545.8 g) and dried in a vacuum oven at 45 C for ¨22 h until a constant weight was achieved. The isolated Intermediate 2 (4597.8 g, 79.7%) was packaged into two 3 mil LDPE bags and stored inside a fiber board drum. HPLC Analysis: 99.4%.
104561 Step 2: N-(0r,41)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-Apyridazine-3-carboxamide. To a clean, dry, 100-L, jacketed, glass reactor equipped with a temperature controller, two pen chart recorder, and a nitrogen bleed was charged dichloromethane (36 L, 7.9 vol), Intermediate 2 (4577.1 g, 1 wt), sodium bicarbonate (1222.0 g), sodium bromide (1097.5 g, 0.24 wt), and purified water (25 L, 5.5 vol). The biphasic mixture was cooled to 0 C over 1 h 11 min then a solution of TEMPO
(15.2 g, 0.0033 wt) in dichloromethane (9 L, 2.0 vol) was added over 32 min while keeping the internal temperature at 0 5 C. Sodium hypochlorite solution (14353.4 g, 3.12 wt) was added over 45 min while maintaining the internal temperature at 0 5 C. The light yellow batch was stirred for an additional 46 min at 0 5 C. The reaction was monitored by HPLC. An additional portion of sodium hypochlorite solution (223,08, 0.05 wt) was added and the batch stirred for an additional 2 h at 0 5 'C. Dichloromethane (9 L, 2.0 vol) was added and the batch stirred for an additional 5 min. The layers were allowed to separate and the upper aqueous layer was discarded to waste. The organic phase was washed (5 min) with a solution of sodium sulfite (1222.2 g, 0.27 wt) in purified water (19 L, 4.2 vol).
The layers were allowed to separate and the upper aqueous layer was discarded to waste.
The organic phase was washed (10 min) with purified water (9 L, 2.0 vol). The layers were allowed to separate and the upper aqueous layer was discarded to waste. The product rich organic phase was charged to the 100-L reactor along with acetonitrile (19 L, 4.2 vol) and vacuum distilled (Jacket Temp. 45 C) to a final volume of 26 L. During the vacuum distillation, additional acetonitrile (37 L, 8.1 vol) was added to the reactor. Acetonitrile (54 L, 11.8 vol) was added and the batch vacuum distilled (Jacket Temp. 45 C) to a final volume of 26 L. The distillation was monitored by 11-1 NMR. Acetonitrile (22 L, 4.8 vol) and purified water (46 L, 10 vol) was charged and the batch temperature adjusted to 20 C.
The batch was stirred for 1 h 26 min then the precipitated solid was isolated by vacuum filtration on a 24-inch, polyethylene, filter funnel. The reactor was rinsed with acetonitrile/purified water 1:1(23 L, 5 vol) and the rinse used to wash the filter cake. After conditioning on the filter under nitrogen for 31 min, the wet-cake was transferred to eight glass drying trays (wet weight 5456.9 g) and dried in a vacuum oven at 45 "C
for --.=44 h until a constant weight was achieved. The isolated Intermediate 3 (4129.8 g, 90.6%) was packaged into two 3 mil LDPE bags and stored inside a fiber board drum. HPLC
Analysis:
96.7%.
104571 Step 3: N-ffir,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexy0-6-(44(4-(2-(2,6-dioxopiperidin-3-y1)-6-fluoro-1,3-dioxvisoindolin-5-Apiperazin-1-ArnethApiperidin-1-yl)pyridazine-3-carboxamide (Compound A). To a clean, dry, 50-1, jacketed, glass reactor equipped with a temperature controller, two single pen chart recorders, and a nitrogen bleed was charged dimethylacetamide (4.3 L, 2.5 vol) and sodium triacetoxyborohydride (2020.4 g, 1.17 wt). The resulting suspension was cooled to 5 5 C over 22 min.
[0458] To a clean, dry, 22-L, jacketed, glass reactor equipped with a temperature controller, a two pen chart recorder, and a nitrogen bleed was charged dimethylacetamide (8.5 L, 4.9 vol), Intermediate 5 (1719.8 g, 1 wt), and Intermediate 3 (2134.0 g, 1.24 wt).
The internal temperature was adjusted to 0 5 C over 39 min then triethylamine (1200 mL, 0.7 vol) was added over 38 min while maintaining the internal temperature <5 C.
[0459] The contents of the reactor were transferred to a separate reactor over 1 h 25 min while maintaining an internal temperature of 5 5 'C. Once the transfer was complete, the first reactor was rinsed with dimethylacetamide (1.1 L, 0.64 vol) and the rinse transferred to the second reactor. The batch was stirred for an additional 61 min at 5 5 C. Reaction was monitored by }LC.
104601 To a clean, dry, 100-L, jacketed, glass reactor equipped with a temperature controller, a two pen chart recorder, and a nitrogen bleed was charged ethanol (21 L, 12.4 vol) and purified water (21 L, 12.4 vol). The internal temperature was adjusted to 10 5 C over 51 min. The contents of the reactor containing the reaction mixture were transferred to the glass reactor over 9 min while maintaining the internal temperature <20 C. Once the transfer was complete, the former reactor was rinsed with dimethylacetamide (1.1 L, 0.64 vol) and the rinse transferred to the glass reactor. The temperature of the batch was adjusted to 50 C over 3 h and held at this temperature for an additional 33 min. The batch was cooled to 20 'C over 81 min, held at this temperature for 69 min, then the precipitated solid was isolated by vacuum filtration on a 24-inch, polyethylene, filter funnel. The reactor was rinsed with ethanol/purified water 1:1 (2 x 11 L, 2 x 6.4 vol) and the rinse used to wash the filter cake. The wet cake was further washed with ethanol (2 x 11 L, 2 x 6.4 vol). After conditioning on the filter under nitrogen for z13 h, the wet-cake (crude Compound A) was transferred to seven glass drying trays (wet weight 11.353 g) and dried in a vacuum oven at 25 C for1 15 h until a constant weight (3382.4 g) was achieved.
EIPLE purity: 99.60 area% (see FIG. 17A).
10461) To a clean, dry, 100-L, jacketed, glass reactor equipped with a temperature controller, a two pen chart recorder, and a nitrogen bleed was charged dichloromethane (54.7 L, 16.2 vol), methanol (6 L, 1.8 vol), and crude Compound A (3375.5 g, 1 wt). The batch was stirred until complete dissolution was observed (27 min). The batch was clarified through a 0.4-micron, in-line filter then distilled under vacuum (jacket temp. 65 C) while adding pre-filtered ethanol (27 L, 8 vol) at such a rate that a total volume of z67.5 L was maintained. Compound A seed crystals (8.4 g, 0.0025 wt) slurried in pre-filtered ethanol (200 mL, CO19788) were added to the batch. Distillation under vacuum (jacket temp. 65 C) was continued while adding pre-filtered ethanol (54 L, 16 vol) at such a rate that a total volume of 67.5 L was maintained. Distillation was monitored by II-I
NMR. The batch was stirred at 20 :I-. 5 C for 4 h, 30 min then the precipitated solid was isolated by vacuum filtration on a 24-inch, polyethylene, filter funnel. The reactor was rinsed with ethanol (13.5 L, 4 vol) and the rinse used to wash the filter cake. The wet cake was further washed with purified water (2 x 13.5 L, 2 x 4 vol) and ethanol (2 x 13.5 L, 2 x 4 vol). After conditioning on the filter under nitrogen for 16 h, the wet-cake was transferred to seven glass drying trays (wet weight 3336.4 g) and dried in a vacuum oven at 25 C for ;.:--99.5 h until a constant weight was achieved and the dichloromethane level had dropped to an acceptable level (450 ppm). The isolated N-((lr,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(44(4-(2-(2,6-dioxopiperidin-3-y1)-6-fluoro-1,3-di oxoi soindoli n-5-yl)piperazin-1-yl)methyl)piperi di n-1-y I )pyri dazi n e-3-carboxami de (Compound A) (3052.4 g, 87%) was packaged into two 3 mil LDPE bags and stored inside an HDPE drum. HPLC Analysis: 99.6 area% (see FIG. 17B).
Example 4: Controls or Critical Steps and Intermediates in the Manufacturing Process for Compound A
104621 At this stage of development, the in-process controls consist of temperature monitoring and high performance liquid chromatography (HPLC) analysis of the reaction mixtures to determine the extent of the reaction. The transformations depicted in Scheme 4 are monitored by expected HPLC endpoints for consumption of the limiting reagent.
104631 The critical in-process controls and target limits for the synthesis of Compound A
are provided in Table 2.
104641Table 2. Critical In-Process Control Points and Acceptance Limits Step In-Process Control Acceptance Lim i t 1 Reaction temperature 90" to 100"C
Consumption of <1.0 % Intermediate 4 remaining Intermediate 4 2 Reaction temperature 0' to 5 C
Consumption of <1.0% Intermediate 2 remaining Intermediate 2 Drying temperature 50' to 60 C
3 Reaction temperature 0 to 5 C
Consumption of <2% Intermediate 5 remaining Intermediate 5 Drying temperature 45 to 65 C
Level of residual solvent IC F1Q3 C
104651 The process development on Compound A includes development of the synthetic route and related processes on a laboratory-scale of 10 to 100 grams and transferred into the kilo-lab for preparation of 28-day toxicology supplies at 1.5 kilogram-scale.
Compound A for use in the preparation of clinical supplies was prepared at a 3-kilogram scale using the same synthetic route and processes employed for the 28-day toxicology supply.

Example 5: Second Generation Synthesis of Intermediate 4 104661 Step 1: Tert-butyl ((1r,4r)--1-hydroxycyclohexyl)carbamate. A solution of K2CO3 (12 kg, 87 mol) in water (60 L) was added (1r, 4r)-4-aminocyclohexanol hydrochloride (12.0 kg, 79.1mol) at 0-10 C. The mixture was stirred at 0-10 C for 1h. Di-tert-butyl dicarbonate (18.1 kg, 83.1mol) was added to the mixture. The resulting mixture was stirred at ambient temperature overnight (20 h). TLC (hexane/ethyl acetate...2/1, SM:
Rf=0;
Product: Rf=0.4) indicated the reaction was complete. The solid was collected by filtration and dried in oven to afford the title compound tert-butyl hydroxycyclohexyl)carbamate (Intermediate 6) (10.13 kg, 60% yield) as white solid.
11-LNMR (400MHz, DMSO-d6): 6(ppm) 1.08-1.20 (m, 4H), 1.36 (s,9H), 1.70-1.78 (m, 4H), 3.14 (s, 11-1), 3.30 (s, 11-1), 4.48 (s, 11-1), 6.65 (d, J...4 Hz, 11T).
104671 Step 2: Tert-butyl (ar,4r)-4-(3-chloro--1-cyanophenoxy)cyclohexyl) carbamate.
Nati (60% in mineral oil, 1110g. 27.8 mol) was added to a solution of Intermediate 6 tert-butyl ((lr,40-4-hydroxycyclohexyl)carbamate (5 kg, 23mo1) in DMF (65 L) at -10 C. The mixture was stirred at -10 C for 1 h. 2-Chloro-4-fluorobenzonitrile (3.6 kg, 23 mol) was added in portions. The resulting mixture was stirred at -10 C for 1 h. TLC
(hexane/ethyl acetate=5/1, 2-Chloro-4-fluorobenzonitrile : Rf=0.7; Product: Rf =0.4) indicated the reaction was complete. The mixture was added to ice-water (200 kg) in portions and stirred at ambient temperature for 20h. The solid was collected by filtration and dried in oven to afford Intermediate 1 (7.8 kg, 95% yield) as white solid. 11INMR (400MHz, DMSO):
o(ppm) 1.33-1.43(m, 131-I), 1.79-1.82 (m, 2H),2.01-2.04 (m, 2H), 4.48-4.50 (m, 1H), 6.85 (d, P.:3.6Hz, 111), 7.11 (dd, J ....8.8 Hz, P.:2.4Hz, 111), 7.67 (d, P.: 1.2 Hz, 1H), 7.83 (d, J =
4.4 Hz, 11-1).
104681 Step 3: 44(1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrik hydrochloride.
Acetyl chloride (13.6 kg, 173mo1) was added dropwise to methanol (35 L) at 0-20 C. After the addition was complete, the mixture was stirred at room temperature for lh.
Intermediate 1 (15.2 Kg) was added to the mixture and the resulting mixture was stirred at room temperature for 2h. TLC (hexane/ethyl acetate=5/1, SM: 1'4=0.4; Product:
Rf=0.1) indicated the reaction was complete. The mixture was concentrated in vacuo.
The residue was taken into methyl tert-butyl ether (25 L) and stirred at ambient temperature overnight (20 h). The solid was collected by filtration and dried in oven to afford 4-0(1r,40-4-aminocyclohexypoxy)-2-chlorobenzonitrile hydrochloride (Intermediate 7) (11.7 kg, 95%
yield). lEINMR. (400MHz, DMSO-d6): 5(ppm) 1.41-1.59 (m,4H), 2.00-2.11 (m, 4H), 3.05 (s, 1H), 4.48-4.55 (m, 1H), 7.14 (dd, J = 8 .8Hz, J=2.4Hz, 1H), 7.41 (d, J=2.4Hz, 1H), 7.85 (d, J...8.811z, 1H), 8.25 (s, 3H).
104691 Step 4: 6-chloro-N-Or,4r)-4-(3-chloro-4-cyanophemo)cyclohexyljpyridazine-3-carboxamide. A 20-1, jacketed reactor was charged with 6-chloropyridazine-3-carboxylic acid (0.490 kg, 3.09 mol, 1.00 equiv), Intermediate 7 (0.888 kg, 3.09 mol, 1.00 equiv), and ethyl acetate (4.4 L, 9 vol). Triethylamine (1.565 kg, 15.5 mol, 5.0 equiv) was added over 47 min and the addition pump lines were rinsed with ethyl acetate (0.5 L, 1 vol). The batch temperature was adjusted to 15-25 C and T3P (3.93 kg of 50% solution, 6.2 mol, 2.00 equiv) was dosed into the reaction over 70 min. The dosing pump was rinsed with ethyl acetate (0.5 L, 1 vol). The batch was aged at 19-20 C for 30 min. The reaction was monitored by HPLC. The reaction was quenched by the addition of 1 N aqueous ITC1 (z-.5 L, 1.6 equiv) over 45 min. The slurry was stirred overnight and then the batch was filtered in a Buchner funnel with filter paper. The kettle and filter cake were rinsed with water (2 x 2.4 L, 2 x 5 vol) and ethyl acetate (2 L, 4 vol). The wet cake was re-slurried in ethyl acetate (2.5 L, 5 vol) for 30 min at room temperature. The batch was filtered and was rinsed with ethyl acetate (1.5 L, 3 vol). However, in-process HPLC analysis of the wet cake showed no change to the level of N-((ir,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-hydroxypyridazine-3-carboxamide (the hydroxyl impurity).
The wet cake (1055 g) was dried in a tray drier at 40-50 C to afford 0.96 kg of Intermediate 4 (79% yield). The water content of the batch was 0.17 wt % by KF titration.
The 1H
NMR spectrum was consistent with the assigned structure and the HPLC purity was 97.3 area% with 2.4 area% of the hydroxyl impurity.
104701 The impure Intermediate 4 (906 g) was charged to a 10-L reactor with DMAc (2.72 L, 3 vol) and the batch was warmed to 50.6 C. IPAc (2.72 L, 3 vol) was added and the batch was maintained at 50 C for 1 h. The temperature was adjusted to 20 C
over 1.5 h and then the batch was filtered. The reactor and filter cake were rinsed with 1PAc (3 x 1.8 L, 3 x 2 vol). The wet cake (1.3 kg) was dried in a tray drier at 30-35 C to afford 0.772 kg of 6-chl oro-N-((lr,40-4-(3-chl oro-4-cyariophenoxy)cycl ohexyl)pyri dazi ne-3-carboxamide (Intermediate 4) (85% yield). The 111 NMR. spectrum was consistent with the assigned structure (see FIG. 20) and the HPLC purity was 98.6 area% with 1.3 area%
of the hydroxyl impurity.
Example 6: Second Generation Synthesis of Intermediate 5 104711 Step 1: 2-(2,6-dioxopiperidin-3-y0-5,6-0fluoroisoindoline-1,3-clione. A
mixture of 4,5-difluorophthalic acid (9.81kg, 1.0eq.), 3-aminopiperidine-2,6-dione (10.38kg, 1.3eq.), CH3COOH (49 kg, 5V) was degassed by purging with nitrogen for three times.
Then CH3COONa (5.375kg, 1.35eq) was added and degassed by purging with nitrogen for three times again. The resulting solution was stirred for 4 hrs at 117-120 C . HPLC
showed the reaction was complete. Then 1120 (147 L, 15V) was added to the mixture slowly at 90 C-120 "C. After cooling to 30 C, the reaction mixture was filtered and the filter cake washed with water (20L, 2V)*2. The filter cake was collected and dried at 50 C to get 12.6 kg 2-(2,6-dioxopiperidin-3-y1)-5,6-difluoroisoindoline-1,3-dione (Intermediate 8) as off-white solid with 88.2% yield. HLNMR conformed to reference spectrum (FIG. 19).
104721 Step 2: teri-butyl 4-('2-(2,6-dioxopiperidin-3-y0-67fluoro-1,3-dioxoisoindolin-5-Apiperazine-1-carboxylate. A 100-L, jacketed reactor was charged with Intermediate 8 (4.50 kg, 15.30 mol, 1.00 equiv), sodium bicarbonate (1.542 kg, 18.35 mol, 1.20 equiv), Boc-piperazine (3.134 kg, 16.82 mol, 1.10 equiv), and NMP (22.5 L, 5 vol). The batch was agitated at 125 rpm. The batch temperature was adjusted to 90 C over 4 h.
The batch was stirred at 90 'V for 16.5 h. The reaction was monitored by HPLC. The batch was cooled over approximately 2 h to 24 C. The cooled reaction mixture was removed from the reactor to a carboy, and the reactor was cleaned with methanol, acetone, and then water.
The reactor was charged with water (43.2 L, 9.6 vol) and acetonitrile (1.8 L, 0.4 vol). The batch temperature was adjusted to 20 'C. The product mixture in the carboy was dosed to the quench solution over 2 h maintaining the temperature at 15-25 C. The precipitated product slurry was transferred to a Nutsche filter. The reactor and filter cake were rinsed with water (2 x 22.5 L, 2 x 5 vol), and the filter cake was conditioned under nitrogen overnight. The wet cake (18.6 kg) was dried in a tray drier at 40-45 C for 11 days to afford 7.05 kg of tert-butyl 4-(2-(2,6-dioxopi peri di n-3-yI)-6-fluoro-1,3-di oxoi soi n dol i n-5-yl)piperazine-1-carboxylate (Intermediate 9) (100% yield). The water content of the batch was 0.6 wt % by KF titration and the 11-1.NMR potency (d6-DMS0) was 84.7 wt %.
The IFINMR spectrum was consistent with the assigned structure (see FIG. 21) and the HPLC
purity was 98.6 area% .
10473) Step 3: 2-(2,6-dioxopiperidin-3-y1)-5-fluoro-6-(piperazin-1-yOisoindoline-1,3-dime hydrochloride. A 30-gallon, Pfaudler reactor was equipped with a sodium hydroxide (2 M) scrubber. The reactor was charged with 3 M hydrochloric acid solution in methanol (70 L, 10 vol). The batch was agitated at 75 rpm. The batch temperature was adjusted to 31.7 "C over 30 min. Intermediate 9 (7.00 kg, 15.20 mol) and methylene chloride (28 L, 4 vol) were charged to a 40-L carboy. The slurry was stirred to dissolve the Intermediate 9.
The solution of Intermediate 9 was charged to the 30-gallon reactor over 6.5 h maintaining the temperature at 30-40 'C. The batch was aged at 35 C for 21 h. The reaction was monitored by HPLC. The batch was cooled to 17.4 C over approximately 30 min.
The slurry was filtered in a Nutsche filter. The reactor and the filter cake were rinsed with a mixture of methanol (15.75 L) and methylene chloride (5.25 L). The wet cake (7.1 kg) was dried in a tray drier at 40-50 C to afford 5.14 kg of product (85 A
yield). The water content of the batch was 3.4 wt % by KF titration and the 11-1 NMR potency (d6-DMS0) was 92.4 wt %. The NMR spectrum was consistent with the assigned structure and the HPLC purity was 97.5 area% .
104741 The batch was then re-purified. To a 100-L, jacketed reactor was charged the previous product (4.95 kg, 12.5 mol) and dimethylacetamide (15.0 L, 3 vol).
The batch temperature was adjusted to 55 C. Water (8.4 L, 1.7 vol) was charged in one portion to the batch and the temperature was re-adjusted 55-65 'C. The mixture was stirred for 44 min to obtain a clear solution. To the batch was charged 2-propanol (40 L, 8 vol) over 1 h maintaining the temperature above 45 C. The batch was seeded at 55 C with Intermediate seeds (5 g). The batch was held at 45-55 C for 20 min and was cooled over 1 h to 25 C. The batch was aged for 17.5 h at 20-25 'C. The slurry was filtered in a Nutsche filter.
The reactor and filter cake was rinsed with 2-propanol (25 L, 5 vol). The filter cake was washed again with 2-propanol (25 L, 5 vol). The wet cake (5.8 kg) was dried in a tray drier at 40-50 C to afford 3.95 kg of product (79% recovery). The water content of the batch was 2.1 wt % by KF titration and the III NMR potency (d6-DMS0) was 98.2 wt %.
The NMR spectrum is shown in FIG. 22 and the HPLC purity was 99.8 area%.

THIRD GENERATION SYNTHESIS
Example 7: Third Generation Synthesis of Compound A
104751 Step 1: 6-(4-(hydroxymethyl)piperidin-1-Apyridazine-3-carboxylic acid (Intermediate 10). The synthetic route to Intermediate 10 is shown below in Scheme 7.
Scheme 7. Synthetic route to Intermediate 10 Hydrazine Ho Br2 Hcry), MeOH.HCI me0".11..;
HO OH Et0H Ni Acetic acid OH 'N OH
OH
0 Fifa"' ra"NC41 POCI3 medty,. NaORtiOH
D 7E".7 Me N,'N MO
CI 1\11'N
intermediate 10 104761 Step 2: N-(ar,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-Apyridazine-3-carborarnide. In a 30-L jacketed reactor equipped with a mechanical stirrer, thermometer and nitrogen bleed was added 6-(4-(hydroxymethyppiperidin-1-yppyridazine-3-carboxylic acid (Intermediate 10) (500 g, 2.11 mol, 1 eq), 4-0(1r,40-4-aminocyclohexypoxy)-2-chlorobenzonitrile hydrochloride (Intermediate 7) (654 g, 2.28 mol, 1.08 eq) and DMAc (2.5 L, 5 vol). To the mixture was added DIPEA (1.092 Kg, 8.43 mol, 4 eq) and ethyl cyanohydroxyiminoacetate (314g. 2.21 mol, 1.05 eq). To the slurry was added 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (525 g, 2.74 mol, 1.3 eq) at once. The temperature of the reaction mixture was increased to ¨40 C. The reaction mixture was kept at internal temperature of ¨40 C for ¨3 h. The reaction was monitored by IPC.
104771 The reaction mixture was diluted with IPAc (5 L, 10 vol) and H2O (DI, 5 L, 10 vol).
The internal temperature was adjusted to 50 5 C while the biphasic mixture was mixing vigorously. The mixture was kept at 50 C for 15 minutes while mixing. The aqueous phase was drained and the organic phase was washed with I-I20 (3 x 5 L, 3 x 10 vol) at 50 C. The organic phase was drained in to a carboy. The aqueous phase was transferred in to the reactor and washed with IPAc (2.5 L, 5 vol) at 50 5 C. All organic phases were combined and transferred in to the reactor (initial KF value: 19754 ppm). The organic phase was concentrated down to ¨3 L (KF value: 4436 ppm). To the mixture was added IPAc (5 L, 10 vol) and distillation was continued to the final volume of 3 L
(KF value:
1169 ppm, <3000 ppm). A thick solid residue was precipitated from the mixture.
The thick slurry mixture was stirred at room temperature for the additional 18 hours. The slurry was filtered and the wet cake was rinsed with IPAc (2 x 5 L, 2 x 2.5 vol). The cake was aged under vacuum for 1.5 hours. The cake was further dried in vacuum oven at 35 C to constant weight. N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperi di n-1-y I )pyri dazi n e-3-carboxami de (Intermediate 2) (830 g, 84%
isolated yield, 99.2% HFLC purity, RRT 1.11: ¨0.13%). The 4-11\TMR spectrum is shown in FIG. 23 10478] Step 3: N-(ar,4r)-4-(3-ehloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-l-y1,pyridazine-3-carboxamide. In a 30-L jacketed reactor equipped with a mechanical stirrer, thermometer and nitrogen bleed was added Intermediate 2 (700 g, 1.49 mol, 1 eq) followed by DCM (5.6 L. 8 vol). To the clear solution was added NaHCO3 (189 g, 2.25 mol, 0.27 wt%), NaBr (168 g, 1.63 mol, 0.24 wt%) and water (DI, 3.5 1, 5 vol) at room temperature. The biphasic mixture was cooled down to <5 C. To the reaction mixture was added solution of TEMPO (23 g, 0.015 mol, 0.0033 wt%) in DCM (1.4 L, 2 vol) at once (no exotherm was observed). To the reaction mixture was added Na0C1 solution (2.18 Kg, 3.12 wt%) in portions while keeping the internal temperature <5 C.
The reaction was monitored by IPC and HPLC. Extra portion of Na0C1 (0.293 Kg, 0.5 wt%) was added to the reaction mixture.
104791 The agitation was stopped and the layers were separated. The organic phase was drained and collected in a clean carboy. The aqueous phase was back extracted using DCM
(1.4 L, 2 vol) and the organic was collected. The aqueous phase was discarded.
The organic phase was transferred in to the reactor and washed with Na2S03 solution (0.5 M, 2.94 L, 4.2 vol). A thick emulsion was formed. To the mixture was added brine (1 L). A
partial separation of the aqueous phase was observed. The clear aqueous phase was removed and to the emulsion was added THF (1.3 L, 10% with respect to the emulsion volume). The stirring was stopped after 10 min and the layers were separated.
The aqueous phase was back extracted using DCM: (1.4 L, 2 vol). The organic phase was collected and the aqueous phase was discarded. All organic phases were transferred into the reactor. To the reactor was added ACN (2.94 L4.2 vol) and the mixture was distilled under reduced pressure to the final volume of 4.5 L. To the reactor was charged ACN (5.7 L, 8.1 vol) and distillation was continued. An IPC of the sample showed 7 wt% of DCM with respect to Intermediate 3 remained. To the reactor was added ACN (4.2 L, 6 vol) and distillation was continued to the final volume of 4 L. Distillation was monitored by IPC. The batch temperature was adjusted to 18 C. To the batch was added ACN (3 L, 4.2 vol) total ACN
volume of 7 L (10 vol). To the mixture was added water (DI, 7 L, 10 vol) and the mixture was stirred at 18 C for 18 hours before filtration. The product was filtered on a Buckner funnel and the wet cake was aged under vacuum for 45 min. The cake was transferred into a glass tray and dried further in vacuum oven at 35 5 C to the constant weight. N-((1r,4r)-4-(3-chl oro-4-cyanophenoxy)cycl ohexyl)-6-(4-formy I pi peri di n-1-yppyri dazi ne-3-carboxamide (Intermediate 3) (676 g, 96% yield, 0.96 wt% ACN content, 94 wt%
potency, 96% HPLC purity, 1.93 % Intermediate 2). The 11-INMR spectrum is shown in FIG.
24.
104801 Step 4: N-(( 1r,4r)-4-(3-chloro-4-cyanophenoxyjcyclohexyl)-6-(444-(2-(2,6-dioxopiperidin-3-y1)-6-fluoro-1,3-dioxoisoindolin-5-y1)piperazin-14methyljpiperidin- 1 -Apyridazine-3-carboxamide. To a clean, dry, 10-L, jacketed, glass reactor equipped with a temperature controller, thermometer, mechanical stirrer and a nitrogen bleed was charged dimethylacetamide (1.24 L, 2.75 vol) and sodium triacetoxyborohydride (528 g, 2.42 eq).
The resulting suspension was cooled to 5 5 'C.
104811 To a clean, dry, 30-L, jacketed, glass reactor equipped with a temperature controller, a thermometer, mechanical stirrer and a nitrogen bleed, was charged dimethylacetamide (2.2 L, 4.9 vol), Intermediate 5 (450 g, 90.7 wt%), and Intermediate 3 (563 g, 94 wt%, 1.1eq). The internal temperature was adjusted to 0 5 then trimethylamine (315 mL) was added over 40 min while maintaining the internal temperature <5 C. The contents of the reactor containing Intermediate 5 and Intermediate 3 were transferred to the reactor containing the sodium triacetoxyborohydride over 40 min while maintaining an internal temperature of to 5 5 'C. Once the transfer was complete, the reactor was rinsed with dimethylacetamide (DMAC) (225 ml, 0.5 vol) and the rinse transferred to the other reactor. The batch was stirred for an additional 1 hour at 5 5 C.
The reaction was monitored by C.
104821 To a clean, dry, 30-L, jacketed, glass reactor equipped with a temperature controller, thermometer and a nitrogen bleed was charged ethanol (5.5 L, 12.1 vol) and purified water (5.6 L, 12.4 vol). The internal temperature was adjusted to 15 5 C. The contents of the reactor containing the process mixture were transferred to the new reactor over 1 hour while maintaining the internal temperature <20 'C. Once the transfer was complete, the former reactor was rinsed with DMAC (200 mL, 0.5 vol) and the rinse transferred to the latter reactor. The temperature of the batch was adjusted to 50 C and held at this temperature for an additional 1 hour. The batch was cooled to 20 C over 81 min, held at this temperature for 1, then the precipitated solid was isolated by vacuum filtration. The reactor was rinsed with ethanol/purified water 1:1 (2 x 2.9 L, 2 x 6.4 vol) and the rinse used to wash the filter cake. The wet cake was further washed with ethanol (2 2.9 L, 2 x 6.4 vol). After conditioning on the filter 1 hour, the wet-cake (crude Compound A) was transferred to three glass drying trays dried in a vacuum oven at 50 C
for 3 days. Constant weight was not achieved.
104831 To a clean, dry, 30-L, jacketed, glass reactor equipped with a temperature controller, a thermometer, mechanical stirrer, condenser, vacuum controller and a nitrogen bleed was charged dichloromethane (15 L, 16.2 vol), methanol (1.66 L, 1.8 vol), and crude Compound A (925 g, 1 wt). The batch was stirred until complete dissolution was observed.
The batch was clarified through a 0.4 micron in-line filter then distilled under vacuum (jacket temp. 65 C) while adding ethanol (5.6 L, 8 vol) at such a rate that a total volume of i 8.5 L was maintained.
Compound A seed crystals (1.85 g, 0.0025 wt) slurried in ethanol (120 mL) were added to the batch. Distillation under vacuum (jacket temp. 65 C) was continued while adding ethanol (10 L, 10 vol) at such a rate that a total volume of 8 L was maintained.
Distillation was monitored by 1PC. The batch was stirred at 20 5 C for 18 hours then the precipitated solid was isolated by vacuum filtration. The wet cake was further washed with purified water (2 x 2 L, 2 x 2 vol) and ethanol (2 x 2 L, 2 x 2 vol). The wet-cake was dried in a vacuum at 25 "C for 24 h until a constant weight was achieved. The isolated N-((lr,40-4-(3 -chl oro-4-cyanophenoxy)cyclohexyl)-6-(4-04-(2-(2,6-di oxopi peri di n-3-y1)-6-fluoro-1,3 -di oxoi soi n dol n-5-yl)pi perazi n-l-yl)methyl)pi peri di n-l-yl)pyri dazi ne-3-carboxamide (Compound A) (850 g, 100%) HPLC Analysis: 99.22 area% (FIG. 18).
The 11-INMR spectrum is shown in FIG. 25.
Example 8. Elucidation of Structure and Other Physical Characteristics of Compound A
104841 Scheme 8. Numbered Carbon Atoms of Compound A.

15 30 /(3.1 NH
41 9 H 17 22 26 28 01 36 37 ist)o NC airs 8 N 13

14 NI' F 35 33 32 ao 39 Ci 3111111 184851 There is a single stereogenic center in the Compound A molecule at carbon 36. The starting materials for Compound A are sourced from achiral precursors, hence the molecule is racemic.
104861 The centers carbon 10 and 7 are meso and by definition have no chirality. The 1,4-trans relationship of the amide and ether on carbons 10 and 7, respectively, is supported by 111 nuclear magnetic resonance (NMR) in conjunction with 2-D nOe NMR.
104871 The drug substance has been characterized by application of various spectroscopic techniques (1H NMR, I3C NMR, mass spectrometry (MS), and Infrared spectroscopy (IR)), all of which support the chemical structure.
104881 NMR Spectroscopy 104891 The 1H and 13C NMR reference spectra of Compound A were taken in the NMR
solvent deuterated dimethylsulfoxide (DMSO-d6). The spectra were obtained on a :Bruker 500 MHz spectrometer. The 1H NMR spectrum is presented in FIG. 4. The 13C NMR
spectrum for Compound A is presented in FIG. 5. Chemical shift assignments for both spectra are also provided in Table 3.
104901 The resonances in both the 1H and 13C spectra were assigned based on 1H-COSY, 1H-13C edited HSQC and 1H-13C HIvIBC experiments. All NMR data acquired support the structure of Compound A.
104911 Table 3. 11-1 and '3C NMR: Chemical Shifts of Compound A

Positiona Chemical Shiftb, c, Integ., 13C Chemical Shiftb, J (Hz) multiplicity, J (Hz)d 1 161.7 2 7.37, 1H, d (2.39) 116.8 3 137.0 4 103.2 7.84, 1H, d (8.77) 135.7 6 7.12, 1H, dd (8.80, 2.39) 115.4 7 4.51, 1H, m 75.6 8, 12 1.50, 2H, m; 2.09, 2H, bi- d (10.14) 29.8 9 1.63, 2H, aq; 1.88, 2H, 29.4 , 11 overlapping br ad 3.85, 1H, m 47.0 10-NH 8.56, 1H, d (8.21) 13 162.5 14 144.2 7.79, 1H, d (9.55) , 126.2 16 7.32, 1H, d (9.71) 112.3 17 159.9 18 22 4.47, 2H, br d (12.97); 3.01, 2H, t 44.4 , (11.78) 19,21 1.82, 2H, br d (11.49); 1.12, 2H, m 29.8 1.90, 1H, overlapping br ad 32.6 23 2.21, 2H, d (7.04) 63.6 24, 27 2.53, 4H, br s 52.8 25, 26 3.24, 4H, br s 49.6 28 145.3 (2Jc.F = 8.55) 29 7.44, 1H, d (4.41-F = 7.38) 113.5 12.8 7 31 166.6 32 166.1 33 123.3 (3JoF = 9.61) 34 7.71, 111, d = 11.43) 111.9 (2Jc-F = 24.92) 157.3 (1.1c-F = 253.69) 36 5.10, 1H, dd (12.87, 5.41) 49.0 111 Chemical Shiftb, C, Integ., Position a 13C Chemical Shifty, J (Hz) multiplicity, J (Hz)d 37 169.9 37-NH 11.09, 1H, s 38 172.7 39 2.59, 1H, in; 2.88, 1H, in 30.9 40 2.02, 1H, m; 2.51, overlapping 22.1 m;
41 116.4 NMR = nuclear magnetic resonance a The numbering used in the structure is for convenience and may not be consistent with IUPAC nomenclature.
b III and 13C NMR chemical shifts were referenced to the resonances due to the NMR solvent at 2.49 and 39.5 ppm, respectively.
d = doublet, dd = doublet of doublet, m = multiplet. s = singlet, t = triplet, br =
broad, aq = apparent quartet, ad = apparent doublet.
d 1H-1H coupling constants in Hertz are given in parenthesis.
104921 Mass Spectrometry 104931 High resolution mass spectrometry (MS) analyses of Compound A were conducted with flow injection analysis using positive ion electrospray [high-resolution electrospray ionization mass spectrometry (HR-ESI)] on a Thermo Orbitrap MS in Fourier Transform mode.
104941 The high resolution mass spectrum of Compound A is presented in FIG. 6, and the major peaks resulting from MS/MS fragmentation of the 812.308 parent ion are presented in FIG. 7.
104951 Further fragmentation of the observed MS/MS ions (MS3) was carried out, yielding the ion map provided in FIG. 8. All ions observed were within 4 ppm of theory by accurate mass, and the ion map serves to further confirm the structure of Compound A.
104961 Infrared Spectrometry 104971 An infrared spectrum of Compound A was obtained on a Bomem MB-102 FTIR
spectrometer equipped with a DuraSampl ER diamond AIR probe. The spectrum is shown in FIG. 9, along with a listing of peaks observed. Key features which lend further support to the structure for Compound A are bands at 2225 cm-I, representing a nitrile stretch vibration, and five peaks between 1774 and 1594, which represent four imide carbonyl vibrations and an amide carbonyl stretch vibration. The fingerprint region from 1500 ---800 cm-1 provides a distinct signature from which to identify Compound A.
Example 9: Summary of Studies to Determine the Particle Size Distribution of Compound A
104981 The particle size statistics for Batch 12070-C-01-72-01 of Compound A
which will be used in preparation of drug product for use in the clinic are shown in Table 4.
104991 Table 4. Particle Size Distribution of Compound A
Batch D (4,3) p In D (10) pro D (50) Jun J D
(90) pm Example 10. Impurities in the Second-Generation Manufacturing Process for Compound A
105001 Batches of Compound A drug substance contain low levels of impurities.
The structure and origin of each known impurity are provided in Table 5. The residual levels of solvents used in the last steps of the synthesis are within the limits as per International Conference on Harmonisation (ICH) Q3C: "Impurities: Guidelines for Residual Solvents." Residual elemental metals meet the limits as described in the United States Pharmacopeia (USP) <232/233> for drug product and follows the principles described in Food and Drug Administration (FDA) and ICH: Guidelines for Elemental Impurities (ICHQ3D).
105011 Table 5. Process Related Impurities in the Compound A Drug Substance Compound Structure Origin Intermediate 3 H
Unreacted starting e 0 material from Step .., amination)( reductive ¨
\ Pe HN
,,-----0' / \
\ ) /
NC __,.,?------u CI
Intermediate 2 OH A process impurity in Intermediate 3 and can be formed as a by-product of the reductive amination in Step 3.
HN This impurity is ¨ECIN11-- also a metabolite in female mouse liver microsomes NC it===' ds CI
Impurity 1 HO A process impurity e0 resulting from over oxidation of Intermediate 2 in Step 2. This ¨ impurity is also a \ tkii metabolite in male human, monkey, HN dog, rat, and mouse C, liver microsomes and hepatocytes NC =(5`
ci los Compound Structure Origin Intermediate 5 H2N-',. o o Unreacted starting CI- N material from Step N
H....0 (reductive amination).
Example 11. Analytical Procedures for Compound A Manufacturing Process 10502) Summaries of the compound specific analytical methods for Compound A
are presented below.
105031 HPLC for Identity, Assay and Impurities 105041 This is a reverse phase high performance liquid chromatography (HPLC) method devised to determine the assay and impurity profile of Compound A for release and stability testing. The method was qualified for its intended uses. Forced degradation studies were performed and used to qualify this method as stability indicating. The HPLC
parameters are listed below in Table 6.
105051 Table 6. HPLC Parameters Column: Waters Atlantis T3, 4.6 x 150 mm, 3 p.m Column Temperature: 45 C
Sample Temperature: ambient Detection: 220 nm and 260 nm Mobile Phase A: 0.1% TFA in Water Mobile Phase B: 0.05% TEA in 75/25 Acetonitri le/methanol Flow Rate: 1.0 mL/minute Injection Volume: 10.0 41, Data Collection Time: 36 minutes Analysis Time: 28 minutes 105061 Gradient:
Time (minutes) % A % B
0 95.0 5.0 1.00 95.0 5.0 10.0 55.0 45.0 20.10 45.0 55.0 24.10 1 5.0 95.0 28.00 5.0 95.0 28.01 95.0 5.0 36.00 95.0 5.0 105071 GC Method 105081 This is a gas chromatography (GC) method used to determine the residual solvents in Compound A drug substance. The chromatographic parameters are listed in Table 7.
105091 Table 7. GC Parameters for Method Number Column DB-624 (60 m x 0.32 mm ID x 1.8 gm) Carrier Gas N2 FID Temperature 280 C
Makeup (N2) Flow 30 mL/min H2 Flow 40 mL/min Air Flow 400 mL/min Control Mode Linear Velocity Column Temperature Program Ramp Temp. ( C) Hold Time 45 5 min C/min 220 3 min Injector Temperature ---------- 200 C --Split Ratio 10:1 Diluent NMP
Run Time 25.5 min FID flame ionization detector; GC gas chromatography; Temp. temperature 105101 The analytical procedures for the determination of assay, impurities, and residual solvents in Compound A drug substance have been qualified. The qualification criteria are provided within the methods. Qualification for high performance liquid chromatography (HPLC) Method was designed to ensure that the HPLC method is suitable for its intended use of assay and impurity determination. The method was qualified for specificity, limit of detection (LOD), limit of quantification (LOQ), linearity, precision and solution stability. Acceptance criteria were established for each studied parameter.
Forced degradation studies determined that method TM05187 is stability indicating and suitable to monitor the assay and impurity determination of Compound A during stability studies.

Qualification of the gas chromatographic (GC) Method was designed to ensure that the method is suitable for its intended use for residual solvent determination.
The method was qualified for specificity, sensitivity, linearity, and repeatability.
Example 12. Stability Studies with Compound A
105111 An exploratory stability study on Compound A is on-going. The stability of Compound A will be studied at 5 C, 25 C/60%RI-1, and 40 C/75%RI-1 with sampling points at 1, 2, 3, and 6 months. Samples will be analyzed using the stability indicating method TEST-05187 (high performance liquid chromatography (HPLC)).
105121 The critical quality attributes of the drug substance Compound A that will be monitored are appearance, purity, assay (wt%), impurities, water content, and x-ray powder diffraction (XRPD). The container and closure system for the stability study consists of double plastic (PE) bags placed inside an high-density polyethylene (HDPE) container.
Data from this study are shown in Tables 8, 9, and 1Ø
105131 Table 8. Stability Data for Compound A Storage at 5 C /- 3 C
Test At Initial Initial Initial Date of Datel Date + 1 Date + 2 Manufacture: Month Months Appearance Yellow Solid Yellow Solid Yellow Solid Yellow Solid Water Content (wt%) 0.27 0.86 0.85 1.0 HPLC Assay (wt%) 97.7 99.5 97.4 97.4 HPLC Purity (%) 98.0 98.4 98.4 98.4 HPLC Impurities (%) RRT 0.50 (Intermediate 0.06 0.06 0.05 0.05 5) RRT 0.89 0.07 0.08 0.07 0.07 RRT 0.90 ND <QI, <Q1, <QT., RRT 0.92 0.07 0.06 <QL 0.06 Riur 0.94 ND ND ND <QL
RRT 0.96 (Intermediate 0.16 0.18 0.18 0.17 2) RRT 1.02 0.39 0.38 0.33 0.29 RRT 1.04 (Intermediate 0.12 0.11 0.09 <QL
3) RRT 1.05 (Impurity 1) <QL ND ND ND
.........
RRT 1.07 . 0.19 0.15 0.15 0.15 RRT 1.23 0.06 0.06 0.05 <QL
RRT 1.32 ND ND ND 0.05 RRT 1.36 (Intermediate 0.05 ND <QL <QT., 9) RRT 1.39 0.67 0.45 0.58 0.61 RRT 1.54 ND <Q1, <QL <QL
Total Impurities (%) 2.0 1.3 1.5 1.5 ___......
XRPD Crystalline Crystalline Crystalline Crystal line 'about 3 months after date of manufacture HPLC = high performance liquid chromatography; ND = <_0.02 %; QL = 0.05 %;
XRPD =
x-ray powder diffraction 105141 Table 9. Stability Data for Compound A Storage at 25 C + 2 C/60 % RH
5%
Test At Initial Initial initial Date of Date' Date + 1 Month Date + 2 Manufactu Months re:
Appearance Yellow Yellow Solid Yellow Solid Yellow Solid Solid Water Content 0.27 0.86 0.93 1.2 HPLC Assay 97.7 99.5 97.3 97.5 (wt%) HPLC Purity (%) 98.0 98.4 98.3 98.3 HPLC Impurities (%) RRT 0.50 0.06 0.06 0.05 0.05 (Intermediate 5) RRT 0.89 0.07 0.08 0.07 0.07 RRT 0.90 ND <QL <QL <QL
RRT 0.92 0.07 0.06 0.07 0.06 RRT 0.94 ND ND ND <QL
.......
RRT 0.96 0.16 0.18 0.18 0.17 (Intermediate 2) RRT 1.02 0.39 0.38 0.34 0.28 RRT 1.04 0.12 0.11 0.07 <QL
(Intermediate 3) RRT 1.05 <QL ND ND ND
(Impurity 1) RRT 1.07 0.1.9 0.15 0.15 0.15 RRT 1.23 0.06 0.06 0.05 0.05 RRT 1.32 , ND Ni) ND <Q1, .
RRT 1.36 0.05 ND <Q1_, ND
(Intermediate 9) .......
RRT 1.39 0.67 0.45 0.57 0.65 RRT 1.54 ND <QL <QL <QL
Total Impurities 2.0 1.3 1.6 1.5 (%) XRPD Crystalline Crystalline Crystalline Crystalline 'about 3 months after date of manufacture HPLC = high performance liquid chromatography; ND .... <0.02 %; QL = 0.05 %;
XRPD
= x-ray powder diffraction 105151 Table 10. Stability Data for Compound A Storage at 40 C + 2 C/75% RH
5%
Test At Initial Initial Initial Date of Date' Date + I Date + 2 , Manufacture: Month Months Appearance Yellow Solid Yellow Solid Yellow Solid Yellow Solid Water Content 0.27 0.86 1.0 1.3 _ HPLC Assay 97.7 99.5 97.3 97.2 (wt%) HPLC Purity (%) . 98.0 98.4 98.3 . 98.3 HPLC Impurities (%) RRT 0.50 0.06 0.06 0.05 0.06 (intermediate 5) RRT 0.89 0.07 0.08 0.06 0.06 .......
RRT 0.90 , ND <QL <QL, <QL
RRT 0.92 0.07 0.06 0.07 0.07 RRT 0.94 ND ND ND <QL
RRT 0.96 0.16 0.18 0.1.8 0.18 (Intermediate 2) RRT 1.02 0.39 0.38 0.34 0.28 RRT 1.04 0.12 0.11 0.08 <Q1., (Intermediate 3) RRT 1.05 <QL ND ND ND
(Impurity 1) RRT 1.07 0.19 0.15 0.14 0.14 R.W.171.23 0.06 0.06 0.05 0.06 RRT 1.32 ND ND ND <QL
RRT 1.36 0.05 ND <QL ND
(Intermediate 9) RRT 1.39 0.67 0.45 0.58 0.63 RRT 1.54 ND <QL <QL <QL
Total Impurities 2.0 1.3 1.6 1.5 (%) XRPD Crystalline Crystalline Crystalline Crystalline 'about 3 months after date of manufacture HPLC = high performance liquid chromatography; ND = < 0.02 %; QL = 0.05 %;
XRPD
= x-ray powder diffraction 105161 Summary: after 2 months at all temperature stations, no increase in impurities nor change in solid properties has been observed. After 5 months from. the date of manufacture, no increase in impurities or change in solid properties has been observed. A
small increase in the water content has been observed.
Example 13. Description and Composition of the Compound A Tablet 105171 Compound A tablets are intended for oral administration. Tablets containing 5 mg and 35 mg of the drug substance were manufactured with a press weight of 100 mg and 700 mg, respectively, from a common granulation. The tablet compositions are listed in Table 11.
105181 Table 11. Composition of Compound A 5 Tablets (5 mg and 35 mg) Strength mg 35 mg Component and Quality mg per % w/vv mg per % w/w Standard Function unit unit Compound A Active 5 5 35 5 Microcrystalline Cellulose .
Filler 45.5 45.5 318.5 45.5 NF, Ph. Eur, JP
Lactose Monohydrate N.F/USP, Ph. Eur, Filler 45.5 45.5 318.5 45.5 JP
Croscarniellose Sodium i _3 2 NF, Ph. Eur, j.P Disntegrant 1 3 Silicon Dioxide NF/USP, Ph. Eur, Glidant 0.5 0.5 3.5 0.5 JP
Magnesium Stearate NF, Ph. Eur, Lubricant 0.5 0.5 3.5 0.5 JP
Total Weight 100 100 700 100 NF/USP: National Formulary/United States Pharmacopoeia; Ph. Eur.: European Pharmacopoeia; JP: Japanese Pharmacopoeia Example 14. Preparation of Spray-Dried Dispersion Intermediate.
105191 Multiple compositions were manufactured at the small scale and evaluated both in vitro (e.g., dissolution, stability, etc.) and in vivo (e.g., bioavailability, exposure levels, etc.). There was no advantage observed with dispersions that incorporated polymers and/or surfactants compared to pure spray-dried Compound A. In order to maintain simplicity and maximize drug load, the pure API spray dried was employed.
105201 One engineering and two clinical batches of spray-dried intermediate have been manufactured. The information shown below is taken from the GNP Manufacturing Batch Record (MBR) of the first clinical batch. Because this originates from an MBR, reference is made to specific pieces of equipment. There is no reason to expect that equivalent manufacturing equipment would not be equally effective.
10521) The process for the preparation of a spray-dried intermediate:
1. Starting from crystalline solid Compound A, prepare a 2.5% (w/w) solution of Compound A in 90%/10% (w/w) dichloromethane/methanol;

2. Spray dry solution in PSD-i spray dryer using SK80-16 nozzle using the following conditions:
Parameter Target Target Range Dryer Inlet Temperature 95 C 65-125 C
Dryer Outlet Temperature 37.5 32.5-42.5 C
System Gas Flow 1850 g/min 1550-2150 g/min Liquid Feed Rate 180 glmin 145-205 g/min Liquid Feed Pressure 450 psig 300-600 psig 3. Collect solid in cyclones and transfer to tray dryer to remove residual dichloromethane and methanol to below ICH guideline levels using a defined temperature/humidity ramp.
105221 Updated Preparation of Spray-Dried Dispersion 10523] The process above was further refined. The updated process is as follows:
I. Starting from crystalline solid Compound A, prepare a 6% (w/w) solution of Compound A in 93%/7% (w/w) dichloromethanelmethanol;
2. Spray dry solution in PSD-i spray dryer using Schlick Model 121 nozzle using the following conditions:
Parameter Target Target Range Dryer Inlet Temperature 95 C 65-125 C
Dryer Outlet Temperature 37.5 32.5-42.5 C
System Gas Flow 1850 g/min 1550-2150 g/min Condenser Temperature -5 C -10-0 "C
Liquid Feed Rate 180 g/min 145-205 Orlin Liquid Feed Pressure 450 psig 300-600 psig 3. Collect solid in cyclones and transfer to filter dryer to remove residual dichloromethane and methanol to below ICH guideline levels under vacuum at between 40 and 60 "C.
105241 Granulation Blends and Tablets of Pure Spray-dried Compound A
105251 Table 12 below shows the composition for the first clinical batch of 5 mg and 35 mg tablets as taken from the GMP MI3R. The actual quantities used in the batch matched the target levels to the decimal indicated. On a percent basis, the composition of the precursor engineering batch and second clinical batch was the same, though the absolute quantities of material employed were different. Again, because it originates from an MBR, the information below references specific pieces of equipment. There is no reason to expect that equivalent manufacturing equipment would not be equally effective.
105261 Table 12. Composition of First Clinical Batches of Tablets of Pure Spray-dried Compound A.
Unit Composition Target batch Component ID Item (w/W3/0) Quantity (g) Purpose 100% Compound Active A Spray-Dried 1 5.00 750.0 Ingredient Intermediate Microcrystalline Cellulose 2 45.50 6825.0 Filler (Avicel PHI 02) Lactose Monohydrate 3 45.50 6825.0 Filler (Fast Flo 316) Croscarmellose Sodium 4 3.00 450.0 Disintegrant (Ac-Di-Sol) Colloidal Silicon Dioxide 5 0.50 75.0 GI idant (Syloid 244FP) Magnesium Lubricant 6 0.25 37.5 Stearate (intragrantilar) :Pregranulation 99.75 14962.5 Blend Totals Magnesium Lubricant 0.15 37.5 Stearate (extragranular) Final Blend 100.00 15000.0 Totals 105271 The process for preparing Tablets of Pure Spray-dried Compound A:
1. Charge Bin blender with Items 1-5 2. At 12 RPM, rotate blender 180 times 3. De-lump blend by passing through U10 Comil with an 032R screen into Bin blender 4. At 12 RPM rotate blender 180 times 5. Screen Item 6 through 20 mesh screen and add to blender 6. At 12 RPM. Rotate blender 48 times 7. Granulate blend through Gerteis Roller Compactor with knurled rolls and 1.25 mm square wire granulator screen 8. Collect granulated material in Bin blender and charge with Item 7 passed through 20 mesh screen 9. At 12 RPM rotate blender 48 times to produce final blend 10. Partition final blend into one vessel for 5 mg tablets and another for 35 mg tablets 11. With 5-station Korsch XL100 and 0.3403"x0.6807" oval tooling press 35 mg tablets with suitable compression force (-14 kN) 12. With 10-station Korsch XL100 and 0.25" SRC tooling, press 5 mg tablets with suitable compression force (-4 kN) 105281 Particle size of granulation used in preparation of clinical supplies was not measured. However, the size distribution, as determined by a sieve analysis, was measured of the engineering batch using the same percent composition and equivalent equipment and is shown FIG. 10.
Example 15. Compound A Drug Product.
105291 Compound A 5 mg and 35 mg tablets were manufactured from a common granulation of spray-dried amorphous Compound A with the following compendia]
excipients:
= Microcrystalline Cellulose = Lactose Monohydrate = Croscamiellose Sodium = Silicon Dioxide = Magnesium Stearate 105301 The tablets were packaged and shipped to the clinical pharmacies in heat-induction sealed high-density polyethylene bottles, that are capped with a lined, polypropylene closure. A silica desiccant canister is included to maintain a low-moisture environment.
105311 Drug Substance Considerations 105321 Compound A is designated as BCS IV (low solubility, low permeability).
The designation is supported by the low in vitro permeability in MDCK cells, and the crystalline solid's low solubility of 1.2 lig,/m1., in pH 6.5 simulated intestinal fluid (SW). This results in the modest oral bioavailability observed in the face of low hepatic clearance when colloid-forming, precipitation-resistant solutions are administered. The compound's amorphous solubility in SIF is 30 ps/mL. A membrane flux experiment was conducted in which a fixed amount of compound was introduced into the donor compartment at various concentrations of the SIF bile salts, and appearance of drug was monitored on the receiver side. The rate of compound permeation was strongly dependent on the concentration of micellar species present in the donor solution (Table 13), indicating that absorption is limited not only by low aqueous solubility, but also by diffusion of solubilized drug across the unstirred water layer adjacent to the intestinal wall. If absorption is limited entirely by solubility, the flux would not change with concentration of such species.
Thus, colloid-forming excipients are not only likely to improve bioavailability through the inhibition of precipitation, but also by providing carriers that rapidly resupply the lumina1 surface with free drug as absorption occurs.
105331 Table 13. Flux Measurements as Function of SIF Concentration Flux SIF (mg/mL) (g-min'-cm-2) 0 0.02 0.09 0.14 0.20 SIF simulated intestinal fluid 105341 The mechanism-based understanding of absorption limitations described above suggested the use of amorphous dispersions as a means of leveraging the higher solubility characteristic of non-crystalline solids. Compound A possesses thermal characteristics compatible with this solubilization strategy. The melting point of neat crystalline material is 290 C, consistent with a high propensity to remain in the crystalline state, and a high glass transition temperature (Tg) of 146 C. Thus, while crystals of Compound A
are quite stable, there is a significant barrier to transforming to a crystalline state from an amorphous form. Indeed, a ramped temperature increase of a partially-crystalline sample does eventually lead to a reciystallization event, but not until a temperature of 200-220 C is achieved. Hence, a very large amount of energy is required to induce the mobility and potential crystallization of amorphous Compound A even in the pure state. As discussed below, this robust resistance to crystallization is preserved even in the presence of water.
105351 A 90-minute non-sink dissolution experiment was conducted in which a Compound A suspension was introduced into pH 2 HCl at a final concentration of I mg/mL, which was then periodically sampled and prepared for analysis via centrifugation. A
shift to pH
6.5 SW was carried out 30 minutes into the experiment. The improved solubility of amorphous solid over the crystalline form is clearly demonstrated in FIG. 11.
Higher concentrations are achieved in the gastric phase of the experiment and sustained in the intestinal phase with spray-dried amorphous Compound A.
105361 Early Formulation Development 105371 Due to the limited solubility of Compound A, early rat PK studies were conducted with solutions of Compound A in a variety of vehicles. Dose-linear exposure escalation in rats using solutions containing solubilizers and precipitation inhibitors demonstrated that compound can be delivered into systemic circulation if sufficient concentrations of absorbable drug can be sustained in the upper gastrointestinal (GI) tract.
105381 Rat Studies with Sprav-Dried Dispersions 105391 Male rats were orally administered Compound A as spray-dried dispersions (SDDs) in aqueous suspension containing 0.5% Methocel A4M at 10 mL/kg. Drug loads of 10,25, and 50% in polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA) were dosed along with loads of 25% with either hydroxypropyl methylcellulose (HPMC) or L-grade hydroxypropyl methylcellulose acetate succinate (HPMCA S-L). This allowed comparison across drug loads for the lead polymer as well as with other polymers at a common drug I oad.

105401 Data from the pharmacokinetic studies described in Table 14 show that use of PVPVA led to better exposures compared to the other polymers, but only at 10%
drug loading, which in turn compared favorably to the solution at a similar dose.
This data led to the selection of the 10:90 Compound A:PVPVA dispersion as the formulation employed in the rat good laboratory practice (GLP)-toxicology study.
105411 While a 100/o drug loaded SDD enabled the rat 28-day GLP toxicology study because of the high dosing volume permitted in preclinical species, such a value is too low to be employed in a human solid dosage form. Performance of pure spray-dried amorphous Compound A achieved the second-highest exposures of all the amorphous solids administered and would maximize strengths of the clinical solid dosage form.
105421 Table 14. Formulations Tested in Rat Pharmacokinetic Studies Dose (mg/kg) Composition Dosage Form AIX (ngxh/mL) Cosolvent + Precipitation 125 Solution 31,700 Inhibitor 10:90 Compound 150 A:PVPVA Suspension 34;537 25:75 Compound 150 A:PVPVA Suspension 10,286 50:50 Compound 150 Suspenion 14,337 AA:PVPVAs 25:75 Compound 150 A:HPMCAS-L Suspension 11,293 25:75 Compound A:HPMC
150 E3 Suspension 10,649 100% Spray-Dried 150 Suspension 19,362 Amorphous Compound A
DMSO = dimethylsulfoxide; HPMC = hydroxypropyl methylcellulose; HPMCAS-L =
L-grade hydroxypropyl methylcellulose acetate succinate; PEG400 = polyethylene glycol 400; PVPVA = polyvinylpyrrolidoneNinyl acetate copolymer 105431 Dog Studies with Spray-Dried Dispersions 105441 Data from the pharmacokinetic studies described in Table 15 show the formulations administering Compound A as 0.5% Methocel suspensions of four different polymer dispersions of the drug (10 mg/kg of active) to fasted, pentagastrin pre-treated male dogs.
Suspensions in dog yielded lower exposure compared to the solution. As a consequence, the solution formulation was used in the 28-day GLP toxicology study. With respect to development of a clinical solid dosage form, however, within the variability of the area under the curve (AUC) values, there is no indication of improved exposure with low drug loaded SDDs. This data, when combined with the experimental results from the rat, suggests that 100% spray-dried amorphous Compound A will be as effective in achieving exposure as a Compound A/polymer combination. Hence, this form of the drug was chosen for incorporation into a solid oral dosage form.
105451 Table 15. Formulations Tested in Dog Pharmacokinetic Studies.
Dog Formulation .AIJC (ngx h/mL) Composition Dosage Form Avg SD
Cosolvent -I- Precipitation Inhibitor Solution 5,705 2,256 90:10:0 Compound A:PVPVA:TPGS Suspension 1,635 309 10:80:10 Compound A:PVPVA:TPGS Suspension 866 190 25:65:10 Compound A:PVPVA:TPGS Suspension 2,486 1,549 80:1.0:1.0 Compound A:PVPVA:TPGS Suspension 1,201 540 DMSO = dimethylsulfoxide; HPMC = hydroxypropyl methylcellulose; HPMCAS-L
L-grade hydroxypropyl methylcellulose acetate succinate; PEG400 = polyethylene glycol 400; PVPVA = polyvinylpyrrolidone/vinyl acetate copolymer 105461 A flux experiment similar to that performed to obtain the data in Table 13 for several amorphous suspensions was conducted with results presented in Table 16. Flux remains constant regardless of polymer inclusion or drug load, thus demonstrating the ability of pure spray-dried amorphous Compound A without polymer to source free, absorbable drug in solution.
105471 Table 16. Flux Measurements of Spray-Dried Amorphous and Crystalline Compound A
Table 0-1 Flux Measurements of Spray-Dried Amorphous and Crystalline Compound A

Flux Donor Compartment Contents ( g-min4-cm-2) Spray-Dried Amorphous Compound A 0.15 10:90 Compound A:PVPVA. 0.15 90:1.0 Compound A:PVPVA 0.11 PVPVA = polyvinylpyrrolidone/vinyl acetate copolymer 105481! The amorphous form of pure Compound A is robust with a high Tg and even higher recrystallization temperature. The glass transition temperature does decrease under the plasticizing conditions of high humidity. However, the value is still well above the commonly applied 40-50 C difference between Tg and any temperature the clinical presentation will encounter. Pure, spray-dried amorphous Compound A is predicted to be more stable under high humidity conditions than is a polymer dispersion as shown in Table 17.
10549) Table 17. Glass Transition Temperatures of Spray-Dried Amorphous Compound A-Containing Solids as Function of Temperature and Relative Humidity.
Temperature/RH ( C/%) Powder 25/0 40/75 1.00% Spray Dried Amorphous Compound A
10% API in PVPVA 114 C 25 C
API = active pharmaceutical ingredient; PVPVA = polyvinylpyrrolidonelvinyl acetate copolymer; RH = relative humidity 105501 In conclusion, in vitro and in vivo data support the use of pure, spray-dried amorphous Compound A API within the clinical formulation.
Example 16. Solvent Screen 10551) A screen was conducted to determine the optimum solvent for use purifying Compound A and for dissolution of crystalline Compound A prior to spray drying. The results of the screen are shown in Table 18.
105521 Table 18. Solvent screening preliminary data.

Solids Solvent system wt%) Temperature Dissolution (.
DCM:Acetone, 53:47%wt. 0.82 RI Not dissolved DCM :Ethanol, 92:8%wt. 2.16 RI Dissolved DCM 0.6 RT Not dissolved DCM:Methanol, 4.2 RT Dissolved 95:5 wt./o. ...
RT Dissolved DCM: M ethanol, 4.75 90:10%wt. 6.6 30 Dissolved 8.1 35 Dissolved DCM:Methanol, 80:20% wt. .RI Dissolved DCM: M ethanol, 70:30% wt. 3.2 RT Turbid solution Methanol 2.8 RT Not dissolved Tl-IF 0.7 RT Not dissolved Example 17. Manufacturing Process Development Spray-Dried Amorphous Compound A Intermediate 10553) Amorphous Compound A produced at small (laboratory) and ¨0.5 kg (demonstration) scales was employed to optimize processing conditions for recovery, and study chemical stability, non-sink dissolution performance, particle size, thermal characteristics, and residual solvent levels. Crystalline Compound A was dissolved in 90:10 dichloromethane:methanol (DCM:Me0H) to afford a concentration of 2.5 wt%
and was then introduced into a spray dryer to create the amorphous state. A two-stage tray-drying procedure was used to remove residual solvents.
105541 Particle size of the dried powder was measured via laser diffraction and is shown in Table 19. As expected, the particle size obtained with a smaller scale dryer are slightly smaller than those resulting from spray drying with a larger dryer. Dv(50) values of 10 gm were reproducibly obtained using the latter equipment. This same, larger dryer supplied material for all tablet development and in vivo testing carried out using spray-dried amorphous Compound A and will also do so for the clinical formulations.
105551 Table 19. Laser Diffraction Particle Sizes of Spray-dried Intermediates.
Dryer Sample Volume-Average Diameter (gm) Dv(10) Dv(50) Dv(90) 8LD35 Small Scale 1 5 11 Scale-Up #1 3 9 18 PSD-1 Scale-Up #2 4 10 20 Demonstration 4 10 20 Dv(10) = size below which 10% of the material volume is present Dv(50)= size below which 50% of the material volume is present Dv(90) = size below which 90% of the material volume is present 105561 Suitable chemical stability of the spray solution and the solvent-damp spray-dried intermediate (SDI) over a period of one week, have been confirmed as shown in Table 20.
105571 Table 20. Chemical Stability of Solvent-damp Spray-dried Amorphous Compound A and DCM/Me0H Spray Solution at 25 C.
Weight Weeks Total Percent of Impurities Compound Sample 25 C (%) A
0 1.17 99.1 Damp Spray-Dried Amorphous Compound A 1 1.20 97.3 2 1.45 96.3 0 1.18 Spray Solution 1 1.10 N/A
2 1.40 DCM dichloromethane; Me01-1 methanol 105581 Finally, from a performance perspective, non-sink dissolution of several amorphous Compound A samples from different manufacturing scales, shown in Figure 12 reconfirms the pH-shift non-sink dissolution profile observed in the initial formulation design phase.
Example 18: Compound A Tablet Development.
105591 Several different compositions of 35 mg strength Compound A tablets (Table 21) were made as laboratory scale prototypes using conventional fillers, glidants, disintegrants, and lubricants for evaluation of chemical stability (Table 22) and dissolution (FIG. 13) both immediately after manufacture and after stress storage conditions (2-weeks at 50 C/75%RH open).
105601 Table 21. Compositions of 35 mg Compound A Tablet Prototypes.
Formulation Reference Al A2 A3 Tablet Strength/ Press Weight ting/mg) 35/700 35/700 35/700 Function Ingredient % of Blend Intra Granular Active Spray-dried amorphous Compound A 5.00 5.00 5.00 Filler Microcrystalline cellulose 44.50 44.50 45.50 Filler Lactose Monohydrate 44.50 44.50 45.50 Disintegrant Crospovidone 3.00 Disintegrant Croscarmellose sodium 3.00 3.00 Glidant Silicon dioxide 0.50 0.50 0.50 Lubricant Magnesium stearate 0.25 0.25 0.25 Extra Granular Disintegrant Crospovidone 2.00 Disintegrant Croscarmellose sodium 2.00 Lubricant Magnesium stearate 0.25 0.25 0.25 Totals: 100.00 100.00 100.00 105611 Table 22. Chemical Stability of Prototype Tablets After 2 Weeks at 50"C/75%RH
Open Total Impurities (wt Sample t= (week) 9/0) Percent of Label 0 1.10 98.7 Formulation Al.
1.67 98.3 0 1.06 98.2 Formulation A2 2 1.92 96.8 0 1.15 99.0 Formulation A3 2 1.74 97.3 105621 Based on the acceptable chemical stability of all compositions and the improved dissolution profile observed with formulation A3, A3 was selected for clinical development.
Example 19: Compound A Manufacturing Process Development of a Spray-Dried Amorphous Compound A Intermediate Product: Characterization and Process Assessment 105631 As demonstrated above, the maintenance of Compound A in the amorphous state is integral to achieving in vivo performance. Hence, effort was applied to assure a thorough understanding of the generation and subsequent use of the Compound A
intermediate product.
105641 The batch analysis for the spray-dried amorphous Compound A
intermediate product is provided in Table 23. This data demonstrates that conversion of Compound A
from a crystalline to an amorphous form via spray drying does not materially affect either the potency or impurity profile. It also confirms the amorphous nature of the spray dried intermediate.
105651 Table 23. Batch Analysis Results for Spray-Dried Amorphous Compound A
Intermediate Product Demonstration Batch (SDI) Contrasted to Input API
In Process Test Specification API SDI
Appearance FIO Light yellow powder DCM (ppm) <600 16 200 Me0H (ppm) <1,000 <1.5 (LOD) ----- <100 (LOQ) --Assay (% label) 98.1 99.1 Impurities?. 0.05%
RRT = 0.50 Area % 0.06 Area %
0.05 0.89 0.07 0.08 0.92 0.07 0.07 0.96 0.16 0.16 1.02 0.39 0.37 1.04 0.12 <0.05 (LOQ) 1.07 0.19 0.1.8 1.23 0.06 0.05 1.36 0.05 <0.05 (LOQ) 1.39 0.67 0.22 Total Impurities 1.84 1.18 D50 (gm) FIO 10 PXRD FIO Crystalline Amorphous SEM FIO No crystallization Morphology or fusing DCM = dichloromethane; for information only; Me0H methanol; LOD limit of detection; LOQ = limit of quantitation; PXRD = powder x-ray diffraction;
RRT =
relative retention time; SEM = scanning electron microscopy 10566) The difference in the low impurity levels is considered to be caused by method variability.
Example 20: Stability of the Amorphous form of Compound A ("the Spray-Dried I ntermediate") 105671 The stability of amorphous Compound A was assessed at three stability conditions:
2-8 C; 25 C/60%RH; and 40 C/75%RH for a period of 12 months.
105681 During stability testing, amorphous Compound A was stored in wire-tied low-density polyethylene bags placed in heat-induction sealed, high-density polyethylene (FIDPE) bottles containing a desiccant canister, and capped with polypropylene-lined closures.
105691 After 6 months of storage at 2-8 C, the purity of the amorphous form of Compound A was >95% (95.7%), with water being the major impurity (0.9%).
105701 After 12 months of storing at 25 C/60%RH, the purity of the amorphous form of Compound A was >97% (97.7%), with water being the major impurity (1.62%).
105711 After 12 months of storing at 40 C/75%RH, the purity of the amorphous form of Compound A was 98%, with water being the major impurity (2.16%, as measured by Karl Fischer titration).
10572) It is noteworthy that under all three storage conditions, there was no evidence of recrystallization of the amorphous form Compound A at any time during these studies.
Example 21. Batch Manufacture of Compound A Tablets 105731 Compound A tablets, 5 and 35 mg, were prepared from a single, common blend.
Prior to blending, Compound A drug substance (DS) is dissolved, then spray-dried to form an amorphous drug product intermediate (amorphous Compound A). Formulas for each strength of the demonstration batches (5 mg and 35 mg tablets) are provided in Table 24 and Table 25, respectively.
105741 Table 24. Demonstration Batch Formula for Compound A Tablets, 5 mg Quantity Per Batch Cornponent Function (g) Compound A Intermediate Product Active Agent 250.05 Microcrystalline Cellulose 2275.04 Avicer'' PH102 (NF, Ph. Eur, JP) Filler Lactose Monohydrate 2275.07 ll ForemostTM 316 (NF/USP, Ph. Eur, JP) Fi er Croscarmellose Sodium 150.04 i sintegrant Ac-Di-Sol (NF, Ph. Eur, JP) D
Silicon Dioxide 25.06 Syloid i 244FP (NF/USP, Ph. Eur, JP) Gldant Intragranular 12.52 Magnesium Stearate (NF, Ph. Eur, JP) Lubricant Extragranular I 0.34a Magnesium. Stearate (NF, Ph. Eur, JP) Lubri cant Total Blend Weight 4998.12b Tablet Press Weight 100 mg Total Number of 5 mg Tablets 6930 a Extragranular magnesium stearate amount adjusted based on granule yield.
b Total weight of common blend, which was appropriately divided to make both 5 mg and 35 mg tablets.
105751 Table 25. Demonstration Batch Formula for Compound A Tablets, 35 mg Quantity Per Batch Component Function Compound A Intermediate Product Active Agent 250.05 Microcrystalline Cellulose Filler 2275.04 Avice0) PH102 (NF, Ph. Eur, JP) Lactose Monohydrate Filler 2275.07 ForemostTM 316 (NF/USP, Ph. Eur, JP) Croscannellose Sodium 150.04 ii Ac-Di-Sol 4' (NF, Ph. Eur, JP) Dsntegrant Silicon Dioxide A 25.06 (dam 244FP (NHUSP, Ph. Eur, JP) Intragranular 12.52 Magnesium Stearate (NE, Ph. Eur, JP) Lubricant Extragranular 10.34"
Magnesium Stearate (NF, Ph. Eur, JP) Lubricant Total Blend Weight 4998.12b Tablet Press Weight 700 mg Total Number of 35 mg Tablets 3500 a Extragranular magnesium stearate amount adjusted based on granule yield.
b Total weight of common blend, which was appropriately divided to make both 5 mg and 35 mg tablets.
105761 Container Closure System for Compound A Tablets 10577) Compound A Tablets, 5 mg and 35 mg, were packaged in heat-induction sealed, high-density polyethylene bottles, 1.00 cc and 500 cc in size, respectively, containing a desiccant, and closed with a child-resistant cap. The primary container closure components are in compliance with relevant United States (US) and European Union (EU) guidelines pertaining to materials that come in contact with food.
Example 22. Batch Formula for Compound A Tablets.
105781 Compound A tablets, 5 and 35 mg, were prepared from a single, common blend.
Prior to blending, Compound A DS was dissolved, then spray-dried to form an amorphous drug product intermediate (amorphous Compound A). Representative formulas for each strength are provided in Table 26 and Table 27.
105791 Table 26. Batch Formula for Clinical Compound A Tablets, 5 mg Batch Target Component Function Quantity (g) Compound A Intermediate Product Active Agent 750 Microcrystalline Cellulose Filler 6,825 Avicerg) PH102 (NF, Ph. Eur, JP) Lactose Monohydrate 6,825 Filler ForemostTM 316 (NF/USP, Ph. Eur, JP) Croscannellose Sodium 450 Ac-Di-Sol ' (NF, Ph. Eur, JP) Disintegrant Silicon Dioxide 75 Glidant 244FP (NHUSP, Ph. Eur, JP) Intragranular 37.5 Magnesium Stearate (NF, Ph. Eur, JP) Lubricant Magnesium Stearate (NF, Ph. Eur, JP) Extragranular 37.5 Lubricant Total Blend Weight 15,000*
Tablet Press Weight 100 mo -Total Number of 5 mg Tablets 21,400 JP = Japanese Formulary; NF National Formulary; Ph. Eur. = European Pharmacopoeia; USP = United States Pharmacopeia *Total weight of common blend, which is appropriately divided to make two batches of tablets.
105801 Table 27. Batch Formula for Clinical Compound A Tablets, 35 mg Batch Target Component Function Quantity (g) Compound A Intermediate Product Active Agent 750 Microcrystalline Cellulose Filler 6,825 Avicel' PH102 (NF, Ph. Eur, JP) Lactose Monohydrate 6,825 Filler ForemostTM 316 (NF/USP, Ph. Fur, JP) Croscannellose Sodium 450 Disintegrant Ac-Di-Sol ' (NF, Ph. Eur, JP) Silicon Dioxide 76 Glidant Syloid 244FP (NHUSP, Ph. Eur, JP) Magnesium Stearate (NF, Ph. Eur, JP) Intragranular 37.5 Lubricant Magnesium Stearate (NF, Ph. Eur Extragranular , JP) 37.5 Lubricant Total Blend Weight 15,000*
Tablet Press Weight 700 mg Total Number of 35 mg Tablets 12,400 JP = Japanese Formulary; NF - National Formulary; Ph. Eur. European Pharmacopoeia; USP = United States Pharmacopeia *Total weight of common blend, which is appropriately divided to make two batches of tablets.
Example 23. Manufacturing and Process Description for the Compound A Tablets.
105811 Compound A Intermediate Product: Compound A was dissolved in a 90/10 (w/w) mixture of dichloromethane (DCM) and methanol (Me0H), both of which are National Formulary (NF) grade, and stirred until a clear, yellow solution of 25 mg/mL
was obtained.
This solution was introduced to a spray dryer. The damp solid output was tray-dried to produce an amorphous solid (amorphous Compound A). This solid was checked for residual DCM and Me0H as an in-process test. A flow diagram of the manufacturing process of Compound A intermediate product is presented in FIG.14.
105821 Tableting: a common dry granulation was used to produce Compound A
tablets.
Amorphous Compound A was blended with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and silicon dioxide in a suitable blender.
The resulting powder was delumped and magnesium stearate added and blended. The blend was granulated using a suitable roller compactor and passed through a screen.
Extragranular magnesium stearate was added and the bulk powder was blended in a suitable blender. The blend was compressed into tablets using a rotary press and the resulting tablets packaged in bulk containers. The flow diagram of the manufacturing process of Compound A tablets is presented in FIG. 15.
105831 Controls of Critical Steps and Intermediates in the Manufacturing Process for Compound A Tablets.
105841 A summary of controls performed at the critical steps of the manufacturing process for Compound A intermediate product and for Compound A tablets are provided in Table 28 and Table 29, respectively.
105851 The residual solvents level in the Compound A intermediate product is a quality attribute that is carefully monitored to assure safety. Acceptance criteria are those specified in the International Council for Harmonisation (ICH) harmonized guidelines for residual solvents Q3C(R6). Tablet properties are monitored to assure consistent size and performance. Additional controls may be added or refilled as drug development progresses.
105861 Table 28. In-process Controls for the Manufacture of Compound A
Intermediate Product.
Critical Step Test Method Acceptance Criteria Spray drying of Residual TEST-099 600 ppm Compound A di ch lorom ethane Spray drying of Residual methanol TEST-099 Ic3000 ppm Compound A
105871 Table 29. In-process Controls for the Manufacture of Compound A
Tablets, 5 mg and 35 mg.
Critical Method Alert Limit (5 Alert Limit (35 Step Test Type mg) mg) Individual Weighing 100 mg 5% 700 mg 5%
press weight Tabl eting Sotax Average Hardness 6.5 kp 2 kp 27 kp 2 kp hardness Tester 105881 Control of Excipients (Compound A., Tablet) 105891 Specifications: The excipients used in the manufacture of 5 mg and 35 mg tablets meet multi-compendial requirements: microcrystalline cellulose (National Formulary (NF), European Pharmacopoeia (Ph. Eur.), Japanese Pharmacopoeia (JP)), lactose monohydrate (NF/USP, Ph. Eur., JP), croscarmellose sodium (NF, Ph. Eur., JP), silicon dioxide (NE/13SP, Ph. Eur., JP), and magnesium stearate (NF, Ph. Eur., JP).
There are no non-compendial excipients used in the manufacturing process or present in the drug product.
105901 Control of Drug Product (Compound A, Tablet) 105911 Specifications for Compound A tablets, 5 mg and 35 mg, are outlined in Table 30 and Table 31, respectively.
105921 Table 30. Specifications for Compound A Tablets, 5 mg Analytical Test Procedure Acceptance Criteria Appearance ------------ TEST-009 Yellow to light-yellow, round tablet The difference between HPLC retention Identity by HPLC TEST-513 time of the sample and that of the main peak in the closest working standard injection is NMT 5%.
Assay (5 mg, % label) TEST-513 90-110% of label claim Related Substances (%) TEST-513 Report all impurities > 0.05%
Report all impurities related to drug product manufacture or degradation >
DP Related Substances 0.05%.
TEST-513*
(%) Total of impurities related to drug product manufacture or degradation 5.
2.5%.
No single unspecified impurity > 1%.
Content Uniformity TEST-513 Meets USP <905>
Dissolution TEST-514 Q > 75% @ T = 45 min DP drug product; HPLC high performance liquid chromatography; NMT not more than; USP = United States Pharmacopoeia; Q = amount of dissolved active ingredient as percentage of labeled content *Value obtained by comparing chromatographic impurity peak areas of drug product with those of corresponding peaks reported in the drug substance Certificate of Analysis and taking the difference.
105931 Table 31. Drug Product Specifications for Compound A Tablets, 35 mg Analytical Test Procedure Acceptance Criteria Appearance TEST-009 Yellow to light-yellow, oval tablet The difference between HPLC retention Identity by HPLC TEST-513 time of the sample and that of the main peak in the closest working standard injection is NMI 5%.
Assay (35 mg, % label) TEST-513 90-11.0% of label claim Related Substances (%) TEST-5I3 Report all impurities? 0.05%

Analytical Test Procedure Acceptance Criteria Report all impurities related to drug product manufacture or degradation DP Related Substances 0.05%.
TEST-513*
(%) Total of impurities related to drug product manufacture or degradation <
2.5%.
No single unspecified impurity > 1%.
Content Uniformity TEST-513 Meets USP <905>
Dissolution TEST-514 Q ?. 75% @ T = 45 min DP = drug product; }PLC = high performance liquid chromatography; NMT = not more than; USP = United States Pharmacopoeia; Q amount of dissolved active ingredient as percentage of labeled content *Value obtained by comparing chromatographic impurity peak areas of drug product with those of corresponding peaks reported in the drug substance Certificate of Analysis and taking the difference.
105941 Analytical Procedures for Compound A Tablets: analytical methods for identity, assay, related substances, content uniformity, and dissolution that ensure quality of Compound A tablets, 5 mg and 35 mg, have been developed. The method summaries are described in the section below.
105951 Table 32. Analytical Procedures for Compound A Tablets Assay Method Number Appearance TEST-009 Identity by HPIA: TEST-513 Assay TEST-513 Related Substances TEST-513 Content Uniformity TEST-513 Dissolution TEST-514 HPLC high performance liquid chromatography 105961 Appearance (Method TEST-009) 105971 Using a light box for uniform illumination, material is examined for color and shape confirmation is referenced to standard color wheels and figures, respectively.

105981 Compound A Identity, Assay, Related Substances, and Content Uniformity by High Performance Liquid Chromatography (HPLC) (TEST-513) 105991 Samples are weighed out, dissolved in 80:20 (v/v) methano1:0.1%
trifluoroacetic acid (TFA) in water, passed through a filter, and injected onto a HPLC with the conditions shown in Table 33.
106001 Table 33. Chromatographic Conditions For TEST-513 Parameter Value Column Waters Atlantis T3, 4.6 x 1.50 mm, 3 pm Column Temperature 45 C
Detection 260 nm Mobile Phase A 0.1% Trifluoroacetic acid in Water Mobile Phase B 0.05% Trifluoroacetic acid in 75/25 acetonitri le/methanol Flow Rate 1.0 mL/minute Injection Volume 10.0 tit Run Time 36 minutes [0601] Identity is reported as the percent difference between HPLC retention time of the sample and that of the main peak in the closest working standard injection.
Potency is determined by comparison of peak area to that of the working standard and reported as percent of label claim. All impurities with peak area 0.05% that are not Compound A
are reported. Impurities specific to drug product manufacture or degradation are obtained by comparing chromatographic impurity peak areas of drug product with those of corresponding peaks reported in the drug substance Certificate of Analysis and taking the difference. A sample of 10 tablets is analyzed to perform a content uniformity assessment, with the results reported per United States Pharmacopeia (USP) <905>.
[0602] Dissolution (Method TEST-514) [0603] Tablets are introduced into a USP II apparatus with 1-liter vessels containing 900 mL (35 mg tablet) or 500 mL (5 mg tablet) of 50 mM Na2HPO4, pH 6.5 with 0.5 wiv%
sodium lauryl sulfate at 37 C using a paddle speed of 75 RPM. Samples are removed at 10, 15, 20, 30, 45, and 60 min, filtered through a 10 p.m full-flow filter, diluted with acetonitrile, injected onto a HPLC with the conditions shown in Table 34.
106041 Table 34. Chromatographic Conditions For TEST-514 Parameter Value Column: Agilent Zorbax SB-C18 4.6 x 150 mm, 3.5 1.1M
Column Temperature 30 C
Detection 260 nm Wavelength 60:40 Water:Acetonitrile, 0.1%TFA (v/v), 0.00025% SLS
Mobile Phase (w/v) Flow Rate 1.0 mIlminute Injection Volume 2 Run Time 4.0 minutes TFA trifluoroacetic acid; SLS sodium latnyl sulfate 106051 Six replicates of each tablet are tested, and results are reported as percent dose dissolved of label claim..
106061 Batch Analyses (Compound A, Tablet) 106071 The clinical batches intended for use in the proposed Phase I clinical trial are produced using the same formula and process as the 5 mg and 35 mg tablet demonstration batches characterized in Table 37 and Table 38, respectively.
106081 Batch Analyses of Compound A Tablets, 5 mg and 35 mg 106091 A description of the demonstration batches of Compound A 5 mg and 35 mg tablets are provided in Table 35, Table 36, and Table 37.
106101 Table 35. Description of Batches of Compound A Tablets, 5 and 35 mg Batch Strength Size and (number Batch of Date of Number tablets) Manufacture Use mg 6930 Aug-2018 Demonstration, stability 35 mg 3500 Aug-2018 Demonstration, stability 106111 Table 36. Batch Analysis Results for Compound A 5 mg Tablets Test Acceptance Criteria Result Light yellow/yellow round Appearance tablet Conforms Identity by ART < 5% Conforms HPLC
Assay 90-110% 98.3 (% label) RRT Area %
0.49 0.06 0.89 0.08 0.92 0.07 Related Report all impurities > 0.05% 0.95 0.17 Substances (%) 1.02 0.32 1.07 0.17 1.23 0.06 1.38 0.52 Report all impurities related to drug product manufacture NR
or degradation > 0.05%
Related Total of impurities related to Substances (%) drug product manufacture or degradation < 2.5%. No 0.00 single unspecified impurity ?
1%.
Content Meets USP <905> Conforms Uniformity Dissolution Q > 75% @ T 45 min Conforms HPLC high performance liquid chromatography; NR none reported; R.T
retention time; RRT = relative retention time; USP = United States Pharmacopeia; Q =
amount of dissolved active ingredient as percentage of labeled content 106121 Table 37. Batch Analysis Results for Compound A 35 mg Tablets Test Specification Result Light yellow/yellow oval Appearance Conforms tablet Identity by ART < 5% Conforms HPLC
A.ssay 90-110% 98.8 (% label) RRT Area %
Related Substances (%) Report all impurities?. 0.05% 0.49 0.05 0.89 0.08 0.92 0.07 0.95 0.17 1.02 0.31 1.07 0.18 1.23 0.05 1.38 0.56 Report all impurities related to drug product manufacture or NR
degradation > 0.05%
Related Substances (%) Total of impurities related to drug product manufacture or 0.00 degradation < 2.5%. No single unspecified impurity 1%.
Content Meets USP <905> Conforms Uniformity Dissolution Q 75% T =: 45 min Conforms HPLC = high performance liquid chromatography; NR = none reported; RI =
retention time; RRT = relative retention time; I3SP = United States Pharmacopeia; Q =
amount of dissolved active ingredient as percentage of labeled content 106131 Characterization of Impurities (Compound A, Tablet) 106141 No additional impurities/degradants were identified as a consequence of drug product manufacture and degradation beyond those already present in the active pharmaceutical ingredient (API).
Example 24: Stability of the Compound A Tablets 106 1 51 The protocol used for the Compound A, 5 mg and 35 mg, is described in Table 38 During stability testing, the tablets were stored in heat-induction-sealed high-density polyethylene (HDPE) bottles containing a desiccant canister, and capped with a polypropylene-lined closure.
106161 Table 38. Stability Protocol for Demonstration Batches of Compound A
Tablets (5 mg and 35 mg) Months Condition Initial 1 3 6 9* 12*

25 C/60%RH .4 \ 4 4 40 C/75%RH
1 I I I .\/
4= Appearance, Assay/Related Substances. Sink Dissolution. Water by KF
*Optional time points; KF = Karl Fischer titration [0617] Summary of Stability Results Phase 1 clinical trial drug product has been prepared using the same formula, process, and equipment.
106181 No change in key quality attributes of Compound A tablets, 5 mg and 35 mg, was observed after 1 month at 40 C/75% relative humidity (RH) with the exception of the relative retention time (RRI)= 1.02 chromatographic peak observed in some samples. The presence and magnitude of this peak is independent of storage conditions and is seen in both tablet strengths. It is thus potentially due to analytical variation.
Likewise, real-time data for 1 month at 25 C/60 /RH show no change in impurity profile.
[0619] After 6 months, all samples 40 C/75% RH are still within specification.
This implies that the samples will have a shelf-life of at least 2 years.
106201 After 24 months, all samples at 25 C/60%RH are still within specification.
106211 Stability data to support the clinical use of 5 mg Compound A tablets, at 2-8 C, 25 C/60%RH, and 40 C/75% RH, 35 mg Compound A tablets, at 2-8 C, 25 C/60% RH, and 40 C/75% RH are presented in Tables 39-44.

10622.1 Table 39. Stability Results at 2-8 C Compound A. Tablets, 5 mg Batch Size: 6930 tablets Packaging: Closed in heat-induction sealed HDPE bottle containing desiccant canister with polypropylene closure Test Acceptance Criteria . Method Initial I Month 3 Month 6 Month Appearance Light yellow/yellow round tablet TEST-009 Conforms Conforms Conforms Conforms t4 Assay OA label) 90-110% TEST-5I3 , 98.3 98.3 95.8 98.7 , t4 c., RRT Area %
RRT Area % RRT Area % RRT Area %
:I
0.49 0.06 0.49 0.05 0.49 0.06 0.46 0.06 4..
0.88 0.08 NR
NR 0.88 0.06 0.87 0.07 0.92 0.07 0.92 0.08 0.91 0.08 0.91 0.09 Related Report all impurities > 0.05% TEST-513 0.96 0.17 0.95 0.16 0.94 0.14 0.95 0.20 Substances (%) 1.02 0.32 1.02 0.40 1.02 0.06 1.02 0.07 1.07 0.17 1.07 0.19 1.07 0.18 1.07 0.18 1.23 0.06 1.23 0.06 1.24 0.06 1.25 0.06 0 1.38 0.52 1.38 0.27 1.36 NR 1.39 0.40 0 ..-..-.., Report all impurities related to sl 4, 0) .., drug product manufacture or TEST-513 NR. NR Mt NR
degradation? 0.05%

Related =
.-Total of impurities related to drug Substances (%) =
product manufacture or ..-NR NR NR
degradation < 2.5% and no single unspecified impurity? 1%
Dissolution Q? 75% 6gT = 45 min TEST-514 Conforms Conforms Conforms Conforms Water by KE (%) None TEST-0268 4.7 4.3 4.2 4.6 HDPE = high-density polyethylene; NR = none reported; LOQ = limit of quantitation; RRT = relative retention time; ND = none detected; Q = amount of dissolved active ingredient as percentage of labeled content; T=Time; KF = Karl Fischer titration. v en ti e cil k..) =
k..) -, =
w -=
-106231 Table 40. Stability Results at 25 C/60%Ril Compound A Tablets, 5 rug Batch Size: 6930 tablets Pacisagiagi Closed in heat-induction sealed HDPE bottle containing desiccant canister with polypropylene closure Test Acceptance Criteria Method initial 1 Month 3 Month I 6 Month Appearance Light yellow/yellow round tablet TEST-009 Conforms Conforms Conforms Conforms t4 Assay OA label) 90-110% TEST-513 98.3 97.8 96.6 98.7 , t4 c., RRT Area % RRT
, Area % RRT Area % RRT Area %
:I
0.49 0.06 0.49 0.05 0.49 0.06 0.46 0.06 4..
0.88 0.08 NR
NR 0.88 0.06 0.87 0.07 0.92 0.07 0.92 0.07 0.91 0.08 0.91 0.09 Related Report all impurities > 0.05% TEST-513 0.96 0.17 0.95 0.16 0.94 0.14 0.95 0.20 Substances (%) 1.02 0.32 1.02 0.38 1.02 0.06 1.02 0.07 1.07 0.17 1.07 0.18 1.07 0.18 1.07 0.18 1.23 0.06 1.23 0.07 1.24 0.06 1.25 0.06 0 1.38 0.52 1.38 0.58 1.36 0.05 1.39 0.40 0 .

.., Report all impurities related to sl 4, 0) t=.> drug pmduct manufacture or TEST-513 degradation? 0.05%

Related =
Total of impurities related to drug c=
=
Substances (%) .
product manufacture or .

NR NR NR
degradation < 2.5% and no single unspecified impurity > 1%
Dissolution Q? 75% g 1 = 45 min TEST-514 Conforms Conforms Conforms Conforms Water by KE (%) None TEST-0268 4.7 4.2 4.6 5.2 HDPE = high-density polyethylene; NR = none reported; LOQ = limit of quantitation; RRT = relative retention time; ND = none detected; Q = amount of dissolved active ingredient as percentage of labeled content. T-Time; KF = Karl Fischer titration. mo en ti e cil k..) =
k..) -, =
w -=
-10624.1 Table 41. Stability Results at 40 C/75(.`/OR1-1 Compound A
Tablets, 5 mg Packaging: Closed in heat-induction sealed HDPE bottle containing desiccant canister with Batch Size: 6930 tablets polypropylene closure Test Acceptance Criteria Method Initial 1 Month 3 Month 6 Month Appearance Light yellow/yellow round tablet TEST-009 Conforms Conforms Conforms Conforms t4 Assay (% label) 90-110% TEST-513 98.3 98.4 96.1 97.4 , t4 c.., RRT Area %
RRT Area % RRT Area (!io RRT Area %
:I
0.49 0.06 0.49 0.06 0.49 0.06 0.46 0.07 4..
0.88 0.08 NR NR NR. NR 0.85 0.05 NR NR NR NR 0.88 0.08 0.87 0.10 NR NR Mt NR 0.89 0.06 NR NR
Related 0.91 0.07 0.92 0.08 0.91 0.12 0.91 0.21 Report all impurities? 0.05% TEST-513 Substances (%) 0.96 0.17 0.95 0.16 0.94 0.14 0.95 0.19 1.02 0.32 1.02 0.41 1.02 0.06 1.02 0.08 0 1.07 0.17 1.07 0.18 1.07 0.19 1.07 0.17 0 .

.., NR NR
NR NR NR NR 1.11 0.09 ...
sl 4, 0) t..4 1.23 0.06 1.23 0.06 1.24 0.06 1.25 0.06 1.38 0.52 1.38 0.65 1.36 0.09 1.39 0.37 =
...

i 0 06 0 89 0. . . .
Report all impurities related to drug 0. "
product manufacture or degradation > TEST-513 NR
NR 0.91 0.05 0.91 0.14 Related 0.05%
1.11 0.09 Substances (N) Total of impurities related to drug product manufacture or degradation 2.5% and no TEST-513 NR NR 0. 1 1 0.28 single unspecified impuiity ?.. 1%
Dissolution Q> 75% (4 T =45 min TEST-514 Conforms Contbrms Conforms Conforms V
en Water by KF (%) None TEST-0268 4.7 4.4 4.9 5.1 ti e HDPE = high-density polyethylene; NR = none reported; LOQ = limit of quantitation; RRT = relative retention time; ND = none detected; Q = amount of dissolved cil b.) active ingredient as percentage of labeled content; T=Time; KF = Karl Fischer titration. =
b.) I-.
-..
o c.a I-.
o vo I-.

106251 Table 42.
Stability Results at 2-8 C Compound A. Tablets, 35 mg Packaging: Closed in heat-induction sealed HDPE bottle containing desiccant canister with Batch Size: 3500 tablets polypropylene closure Test Acceptance Criteria Method I Initial I Month 3 Month I _______ 6 Month _ Appearance Light yellow/yellow round tablet TEST-009 Conforms Conforms Conforms Conforms k4 Assay (% label) 90-110% , TEST-513 98.8 100.2 95.8 97.1 ..-k4 ---- ......
c..., RRT Area % RRT
Area % RRT Area % RRT Area %
0.49 0.05 0.49 0.05 0.48 0.05 0.46 0.06 4..
0.88 0.08 0.89 0.11 0.87 0.06 0.87 0.07 0.92 0.07 0.92 0.07 0.91 0.07 0.91 0.08 Related 0.95 0.17 0.95 0.16 0.94 0.13 0.94 0.21 u. Repo all impurities > 0.0P/0 TEST-513 Substances (%) 1.02 0.31 1.02 0.50 NR NR 1.02 0.08 1.07 0.18 1.07 0.17 1.06 0.19 1.07 0.18 1.23 0.05 1.23 0.06 1.23 0.06 1.25 0.07 0 NR NR 1.36 0.06 NR NR NR Mt .
w , ,.., 1.37 0.56 1.38 0.65 1.35 0.06 1.39 0.59 , , 4.
.
., 4.
Report all impurities related to drug ., product manufacture or degradation TEST-513 NR
1.02 0.11 NR 0.94 0.05 ., ., , ?0.05%
, , Related w , Substances (%) Total of impurities related to drug product manufacture or degradation 0.11 NR. 0.05 5.: 2.5% and no single unspecified impurity? 1% _...... ___ ........
_________________________________________ ___ Dissolution Q. ? 75% (Ø T =45 min TEST-514 Conforms Conforms Conforms ----------- Conforms Water by KF (%) None TEST-0268 4.2 4.1 4.2 4.3 HDPE = high-density polyethylene; NR - none reported; LOQ = limit of quantitation; RRT - relative retention time; ND = none detected; Q = amount of dissolved .0 en active ingredient as percentage of labeled content; T-Time; KE = Karl Fischer titration. ti e ci) k..) =
k..) ...
, =
w ...
=
,D
...

106261 Table 43. Stability Results at 25 C/60(.`/OR1-1 Compound A
Tablets, 35 rug Packa_gia. Closed in heat-induction sealed I1DPE bottle containing desiccant canister with Batch Size: 3500 tablets polypropylene closure Test Acceptance Criteria Method Initial 1 Month 3 Month 6 Month i4 Appearance Light yellow/yellow round tablet TEST-009 Conforms Conforms Conforms Conforms Assay (% label) 90-110% TEST-513 98.8 100.9 92.4 92.4 , i4 c., RRT Area % RRT
Area % RRT Area % RRT Area %
:I
0.49 0.05 0.49 0.05 0.48 0.05 0.46 0.06 4 = .
0.88 0.08 0.89 0.11 0.87 0.06 0.87 0.07 0.92 0.07 0.92 0.07 0.91 0.07 0.91 0.12 Related Report all impurities ? 0.05% TEST-513 0.95 0.17 0.95 0.16 0.94 0.13 0.94 0.20 Substances (%) 1.02 0.31 1.02 0.49 1.02 0.05 1.02 0.08 1.07 0.18 1.07 0.18 1.06 0.18 1.07 0.18 1.23 0.05 1.23 0.06 1.23 0.06 1.25 0.07 0 1.37 0.56 1.38 0.56 NR NR 1.39 0.48 .
w , _ ., .
1-. Report all impurities related to drug , vs p)duct manufacture or degradation? TEST-513 NR 1.02 0.10 NR 0.91 0.05 ps, 0.05%
" ps, Related Substances (%) Total of impurities related to drug 6;
w product manufacture or degradation S
, TEST-513 NR 0.10 NR 0.11 2.5(%, and no single unspecified impurity? 1%
Dissolution Q> 75% @ T = 45 min ---------------------- TEST-514 Conforms 1 Conforms Conforms Conforms +
Water by KF (/0) None TEST-0268 4.2 I 4.1 4.3 4.4 I-1DPE = high-density polyethylene., NR = none reported; LOQ = limit of quantitation; RRT = relative retention time; ND ..., none detected; Q = amount of dissolved active ingredient as percentage of labeled content; T=Time; KF = Karl Fischer titration. v en ti e cil k..) =
k..) -, =
w -=
-106271 Table 44.
Stability Results at 40 C/75(.`/OR1-1 Compound A Tablets, 35 mg Batch Size: 3500 tablets Packaging: Closed in heat-induction sealed I1DPE bottle containing desiccant canister with polypropylene closure Test Acceptance Criteria Method Initial I
Month 3 Month 6 Month Appearance . Light yellow/yellow round tablet TEST-009 Conforms Conforms Conforms Conforms 0 t4 Assay (% label) 90-110% TEST-513 98.8 99.9 87.4 95.4 r4 , MT Area % RRT
Area (% RRT Area % RRT Area % t4 c.., 0.49 0.05 0.49 0.06 0.48 0.06 0.46 0.07 :I
4..
NR NR NR NR NR NR. 0.85 0.10 0.88 0.08 0.89 0.11 0.87 0.08 0.87 0.16 NR NR NR NR NR NR 0.88 0.05 0.9/ 0.07 0.92 0.09 0.91 0.15 0.91 0.21 Related Report all impurities > 0.05% TEST-513 0.95 0.17 0.95 0.15 0.94 0.13 0.94 0.20 Substances (%) 1.02 0.31 1.02 0.51 1.02 0.05 1.02 0.08 1.07 0.18 1.07 0.17 1.06 0.16 1.07 0.17 0 1.23 0.05 1.23 0.06 1.23 0.06 1.11 0.06 ..
0, ..
WI
.4 4.
Mt NR NR NR NR NR 1.25 0.07 co cp, 1.37 0.56 1.38 0.58 1.35 0.10 1.39 0.39 , NR NR 1.48 0.05 NR NR 1.50 0.05 ..

, 0.85 0.10 ..
1.02 0.12 0.87 0.09 Report all impurities related to 0.88 0.05 drug product manufacture or TEST-513 Mt NR
0.91 0.08 degradation > 0.05%
0.91 0.14 Related 1.48 0.05 1.11 0.06 Substances (%) .
1.50 0.05 mu n Total of impurities related to drug product manufacture or 0.17 0.08 0..49 cil degradation 5. 2.5% and no single b.) o unspecified impurity? 1%
b.) I-.
_______________________________________________________ ......._ -.
Dissolution Q> 75% @ T = 45 min ------------- TEST-514 Conforms Conforms Conforms Conforms o ca I-.
o Water by KF (%) 1 None TEST-0268 4.2 4.3 4.8 5.7 vo .
I-. 1-1DPE = high-density polyethylene; NR = none reported; LOQ = limit of quantitatiom RRT - relative retention time; ND = none detected; Q = amount of dissolved active ingredient as percentage of labeled content; T=Time KF = Karl Fischer titration.

FOURTH GENERATION SYNTHESIS
Example 25: Fourth Generation Synthesis of Compound A
106281 Step 1: N-Or,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethApiperidin-l-Apyridazine-3-carboxamide (Intermediate 2) 106291 To a 260 L glass-lined carbon steel jacketed reactor was charged Intermediate 10 (7.00 kg), Intermediate 7 (8.89 kg), 2-pyridinol 1-oxide (HOPO) (491.4 g), and dimethylacetamide (26.32 g), under nitrogen. The reaction mixture was agitated at 110 rpm (allowed range: 70 to 150 rpm) and cooled to approximately 10 C (allowed temperature range: 5 C to 15 C) over 39 minutes. To the reactor was charged N ,N
Diisopropy I ethy lamine (D1PEA) (4193.0 g) and the reaction mixture was agitated and the temperature re-adjusted back to approximately 10 C (allowed temperature range: 5 C to

15 C) over 47 minutes, and the mixture held for a further 32 minutes.
Agitation was halted, and the reactor was charged with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) (5936.0 g) and the reactor was purged for 6 minutes. The reaction mixture was agitated at 110 rpm, and dimethylacetamide (6580.0 g) was added and the temperature was adjusted to approximately 20 C (allowed temperature range: 10 C to 30 C) over 1 hour and 8 minutes. Agitation was maintained and the reactor was held at approximately 20 C
for 16 hours. At the end of 16 hours, in-process control (1PC) showed 0.3%
area (acceptance criterion: < 1.0% area) of Intermediate 10, indicating completion.
106301 To the reactor was charged tap water (35.0 kg), producing a thick slurry. The reactor was agitated at approximately 140 rpm (allowed range: 100 to 180 rpm) and heated to approximately 60 "C (allowed temperature range: between 55 C to 65 C) over the course of 1 hour and 15 minutes. To the reactor was charged additional tap water (35.0 kg) and isopropyl acetate (73.08 kg). The reactor temperature was adjusted to approximately 78 C
(allowed temperature range: 73 C to 83 C) and held for 40 minutes, during which time the slurry dissolved, and two layers formed. The contents of the reactor were allowed to settle for 3 hours at approximately 78 C. The reactor was purged with nitrogen and the bottom aqueous layer was removed.
106311 To an 800 L glass-lined carbon steel jacketed reactor was charged isopropyl acetate (11.90 kg), followed by the organic layer from the 260 L reactor. A sodium chloride solution (77.0 kg, 9.1% w/w) was charged, followed by isopropyl acetate (60.90 kg). A
biphasic solution was formed, and the mixture was heated to approximately 78 C (allowed temperature range: 73 C to 83 C) over 47 minutes under agitation. The mixture was agitated for 4 hours and 5 minutes at approximately 78 C. The hot mixture was filtered through Celite 545 into the 260 L reactor. The 800 L reactor was rinsed with isopropyl acetate (23.80 g), which was filtered and added to the 260 L reactor. The 260 L reactor was heated to approximately 78 'C (between 73 "C to 83 C) over 3 hours and 6 minutes and the contents were allowed to settle for 4 hours and 1 minute. The reactor was purged with nitrogen and the bottom aqueous layer was removed.
106321 The reactor was agitated at approximately 110 rpm (between 90 and 110 rpm). To the reactor was charged sodium chloride solution (76.3 kg, 9.1% w/w), and a biphasic solution was formed. The reactor was heated to approximately 78 C (allowed temperature range: 73 C to 83 C) over 1 hour and 54 minutes and the temperature was held for 31 minutes. Agitation was stopped and the contents were allowed to settle for 3 hours and 11 minutes. The reactor was purged with nitrogen and the bottom aqueous layer was removed.
106331 The contents of the reactor were concentrated under vacuum distillation at 75 C
(allowed temperature range: 70 C to 80 C) to approximately 42 L. Isopropyl acetate (6.09 kg) was added and the reactor was heated to approximately 80 C (allowed temperature range: 70 C to 85 "C) under agitation. The reactor was held for 1 hour and 2 minutes at approximately 80 C and then cooled to approximately 20 C (allowed temperature range:
15 "C to 25 C) over 6 hours and 28 minutes. The reactor was held at approximately 20 C
for 4 hours and 31 minutes. The resultant slurry was quickly transferred to an electrically agitated Hastelloy filter dryer with an 8 gm polypropylene filter cloth. The slurry was filtered under vacuum, and the mother liquor was used to rinse the reactor.
The contents of the reactor were added to the filter dryer and filtered under vacuum. The solid cake was washed twice with isopropyl acetate (9.17 kg x 2) and filtered under vacuum.
The resulting cake was dried under vacuum with a jacket temperature of 60 C (allowed temperature range: 55 "C to 65 C) until total volatiles (by moisture analyzer) not more than 1.0% w/w (6 hours and 1 minute). The dryer was subsequently cooled, and the cake was collected to afford Intermediate 2 (10.90 kg, 79%). Release results are shown below in Table 45:
Table 45: Release results for Intermediate 2:

Test Name Specification Result Description White to brown solid Conforms Identification (by 1R) Conforms to ref. spectrum Conforms Purity (by UPLC) Not less than 96.0% (area) 99.7% (area) Related Substances (by HPLC) Not more than 0.5%
(area) Not detected Intermediate 10 Alert level: More than 0.15 %(area) Related Substances (by HPLC) Not more than 0.5%
(area) Not detected Intermediate 7 Alert level: More than 0.15 %(area) Related Substances (by HPLC) Report result by RRT in %
(area) RRT 0.907: 0.07/o(area) Any individual impurity Alert level: More than 0.15 %(area) RRT 1.204:
0.20%(brea) RRT 1.218 Less than 0.05 % (area) Related Substances (by HPLC) Not more than 2.0%
(area) 0.2% (area) Total impurities 106341 Step 2: N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexy0-6-(4-formylpiperidin-1-Apyridazine-3-carboxamide (Intermediate 3) 106351 To an 800 L glass-lined carbon steel jacketed reactor, under nitrogen, Intermediate 2 (10.80 kg), sodium bromide (4.75 kg), sodium bicarbonate (3.89 kg) were added. The reactor was purged with nitrogen (x3), and deionized water (129.6 kg), and dichloromethane (186.73 kg) were subsequently added. The reactor was then allowed to agitate at 50 rpm (allowed range: 30 to 70 rpm) for 1 hour and 39 minutes.
106361 Agitation was halted and (2,2,6,6-tetram ethyl pi peri di n-l-yl)oxyl (TEMPO) (35.64 g) was added over 40 mins. The reactor was purged with nitrogen (x 3), and the reaction subsequently charged with dichloromethane (7.18 kg). The reactor was then allowed to agitate at 50 rpm (allowed range: 30 to 70 rpm). The reactor was further charged with isopropyl alcohol (2.81 kg) and dichloromethane (7.18 kg). Agitation was increased to 110 rpm (allowed range: 105 to 115 rpm) and the reaction mixture was allowed to adjust to 20 C (allowed temperature range: 15 C to 25 C), over 33 minutes. Once adjusted, ensuring all solids were dissolved, the reaction mixture, at this temperature and agitation speed, was held for 2 hours and 5 minutes.
106371 The reaction mixture was then cooled to ---2 (allowed temperature range: ¨3 C
to 0 C) over 2 hours and 1 minute, and a sodium hypochlorite solution (34.85 kg) was then added over 40 minutes. ensuring the temperature was maintained between ¨3 'C and 0 C (allowed temperature range: --3 C and 3 "C), with agitation maintained at approximately 110 rpm (allowed range: 105 to 115 rpm). The addition rate and batch temperature are critical due to the exothermic nature of the reaction.
Deionized water (5.40 kg) was then added through the transfer line used in the sodium hypochlorite transfer, ensuring the temperature was maintained between -3 C and 0 'C. The mixture was then subsequently held at -2 C (allowed temperature range: -3 C and 3 C) for 1 hour and 2 minutes. After 1 hour, the in-process control (1PC) showed 0.3% area (acceptance criterion:
< 1.0% area) of Intermediate 2, indicating reaction completion.
106381 The reaction mixture was allowed to warm to 20 C (allowed temperature range:
15 C and 25 C), and agitation held at 90 rpm (allowed range: 80 to 100 rpm), and the reaction mixture was charged with acetic acid (4.104 kg), and the mixture held for 2 hours and 37 minutes, upon which a biphasic solution formed. An electrically agitated Hastelloy filter dryer with a 3-5 Jim polypropylene filter cloth, was charged with Celite 545, and dichloromethane (24. 6 kg) subsequently filtered through. A portion of the reaction mixture was filtered into a 260 L reactor, and the remaining mixture subsequently transferred into a 100 L reactor, and the 800 L reactor rinsed with dichloromethane (28.73 kg), which was filtered and added into the 100 L reactor. The 800 L reactor was rinsed with dichloromethane and filtered. The mixture was transferred from both the 260 L, and the 100 L reactor, back into the 800 L reactor, subsequently rinsing both with dichloromethane (5.40 kg x 2).
106391 Agitation was halted and the mixture allowed to settle into two phases for 3 hours and 25 minutes. The organic phase that separated was transferred into a 260 L
reactor. The organic layer was transferred back into the 800 L, and the 260 L vessel subsequently rinsed with dichloromethane and the contents transferred into the 800 L reactor.
Deionized water (108.0 kg) was added and the reactor allowed to agitate and the temperature increased to 20 C and the content held at this agitation and temperature for 49 minutes.
Agitation was halted and the mixture allowed to settle over 2 hours and 14 minutes, and two layers formed. The organic layer was transferred into the 260 L reactor, and the aqueous layer discarded appropriately.
106401 The mixture was then concentrated by distillation, under normal atmosphere at 40 C (allowed temperature range: 35 C to 45 C) maintaining the volume approximately between 38-49 L by replenishing as required with tetrahydrofuran allowing the temperature to increase to 60 C (allowed temperature range: 55 C to 65 C) and the final volume approximately 46 L. The contents of the reactor were then concentrated under vacuum distillation, replenishing with tetrahydrofuran as required, at 60 C (allowed temperature range: 55 C to 65 C) until S 1.0% v/v of dichloromethane remained.
106411 Recrystallization was undertaken by the addition of n-heptane (29.38 kg) (65 C), and held for 1 hour and 10 minutes, maintaining a temperature of approximately 65 "C.
until a thick slurry was obtained. The slurry was subsequently cooled down slowly to 20 C (allowed temperature range: 15 C to 25 C) by 4 hours and 34 minutes (temperature should not reach below 20 "C before 4 hours), and held at 20 "C for an additional 6 hours and 53 minutes. The resultant slurry was quickly transferred to an electrically agitated Hastelloy filter dryer with an 8 gm. polypropylene filter cloth and the slurry was filtered under vacuum. The cake was washed twice with a tetrahydrofuran (4.86 kg) and n-heptane (3.67 kg) solution (x 3) and filtered under vacuum. The resulting cake was dried under vacuum with a jacket temperature of 50 C (allowed temperature range: 45 C
and 55 C) for 8 hours and 2 minutes, and then increasing the jacket temperature of 75 C
(allowed temperature range: 70 C and 80 C) for 7 hours and 42 minutes, until total volatiles (by moisture analyzer) not more than 1.0% w/w. The dryer was subsequently cooled, and the cake was collected to afford Intermediate 3 (1Ø20 kg, 95%). Release results are shown below in Table 46.
106421 Table 46: Release results for Intermediate 3:
Test Name Specification Result Description White to light brown solid Conforms Loss on Dtying Not mote than 1.5% wiw 0.7% (w/w) (2 gram at 120 CC) Identification (by HPLC) Retention time of the main peak in the Conforms sample solution is consistent with reference standard (Not more than 5%) Purity (by HPLC) Not less than 95.0% (area) 99.0% (area) Related Substances (by HPLC) Not more than 1.5% (area) 0.3 % (area) intermediate 2 Related Substances (by HPLC) Not more than 3.0% (area) 0.7% (area) Empurity 1 Related Substances (by HPLC) Not more than 0.50% (areal Less than Major unspecified impurity 0.056/0(area) Related Substances (by HPLC) Report results 0.06% (area) at RRT 1.24 Alert limit: More than 0.35% (area) Related Substances (by HPLC) Report results RRT 1.24: Less than Any other unspecified Individual Alert limit: More than 0.15% (area) .. 0.05% (area) Impurity RRT 1.42 Less than 0.05% (area) Identificat ion by I R ) Report result Report test 106431 Step 3: N-(ar,479-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(44(4-(2-(2,6-dioxopiperidin-3-y1)-6-fhwro-1,3-dioxvisoindolin-5-Apiperazin-l-AmethApiperidin-1-yl)pyridazine-3-carboxamide (Compound A) 106441 To a 260 L glass-lined carbon steel jacketed reactor, under nitrogen, Intermediate 3 (8.48 kg), Intermediate 5 (7.62 kg), and dimethylacetamide (38.45 kg) were added. The reaction mixture was agitated at 110 rpm (allowed range: 80 to 130 rpm) and allowed to cool to 0 C (allowed range: ¨5 C to 5 C) over 1 hour and 26 minutes. To this was added N-methylmorpholine (4.50 kg), and dimethylacetamide (0.751 kg), and the reaction heled at 0 C and 110 rpm agitation for 3 h and 7 mins.
106451 In a 100 L reactor, under nitrogen, a solution of sodium triacetoxyborohydride (STAB) (5.66 kg), in dimethylacetamide (21.60 kg) was prepared, and the solution allowed to agitate at 110 rpm (allowed range: 90 to 120 rpm), at 20 C (allowed temperature range:
15 C and 25 C for 6 hours and 24 minutes. The STAB/dimethylacetamide solution was slowly added to the reaction mixture contained in the 260 L reactor over 2 hours, maintaining the temperature at 0 C (allowed temperature range: ¨5 C to 5 C) and agitation at 110 rpm (allowed range: 80 to 130 rpm). Upon addition completion, the reactor was washed with dimethylacetamide (5.00 kg), subsequently cooled to 0 C, and its contents added to the reaction mixture in the 260 L reactor over 20 minutes, ensuring the temperature and agitation of 0 C and 110 rpm, respectively, were maintained.
The reaction mixture was held at 0 C (allowed temperature range: ¨5 C to 5 C), 110 rpm for 6 h and 43 min. At the end of the 6 h and 43 mins, the in-process control ([PC) showed 0.7% area (acceptance criterion: < 2.0% area) of Intermediate 3, indicating reaction completion.

106461 Recrystallization was undertaken by charging the reactor vessel with absolute ethanol (40.78 kg), and deionized water (51.71 kg), under nitrogen, and allowing it to heat at 50 C (allowed temperature range: 45 C to 55 C) over 1 hour and 14 minutes, and then further held at this temperature for 1 hour and 24 minutes. The mixture was then allowed to cool to 20 'C (allowed temperature range: 15 to 25) and held at this temperature for 4 hours and 3 minutes. The mixture was transferred to an electrically agitated Hastelloy filter dryer with 3-5 gm polypropylene filter cloth. The mixture was filtered under vacuum and the mother liquor was used to rinse the reactor, and was subsequently refiltered.
106471 An absolute ethanol:water (deionized) wash solution was prepared by mixing absolute ethanol (11.51 kg), and deionized water (14.60 kg). The wash was used to rinse the reactor, and the filter cake was washed using this solution. The ethanol :water wash was repeated. The filter cake was agitated (x 3) forming a slurry that was subsequently allowed to settle. The filter cake was further washed with absolute ethanol (23.02 kg x 4), agitating the filter cake and sufficiently allowing the solid to del iquor.
106481 The solid filter cake was dissolved in a solution of dichloromethane (155.12 kg) and methanol (9.26 kg), and the resultant solution subsequently transferred into an 800 L
reactor through a 0.2 gm polytetrafluoroethylene capsule filter. The filter dryer was rinsed twice with dichloromethane/methanol, and the rinse solutions were filtered through a 0.2 gm polytetrafluoroethylene capsule filter into the 800 L reactor. The mixture was then subject to atmospheric distillation, under normal atmosphere at 45 C (allowed temperature range: 35 C to 50 'C) maintaining the volume by replenishing as required with absolute ethanol to the final volume of approximately 292 L, and a slurry was obtained.
The temperature was then allowed to increase to 55 C, maintaining the volume by replenishing as required with absolute ethanol to the final volume of approximately 292 L.
The contents of the reactor were then subject to vacuum distillation, replenishing with absolute ethanol as required, at 55 "C (allowed temperature range: 45 C to 65 C), to the final volume of approximately 300 L. The vacuum distillation step was repeated until < 1.0%
v/v of di chlorom ethane remained.
106491 The temperature of the mixture was then adjusted to 55 C (allowed temperature range: 50 C and 60 C), and agitation maintained at approximately 100 rpm (allowed range: 90 to 110 rpm) over 30 minutes, and then subsequently held at 55 C for 34 minutes.

The mixture was then allowed to slowly cool to 20 C (allowed temperature range: 15 C
and 25 C), over 3 hours and 59 minutes (temperature should not reach below 20 C before 3 hours), and then held at 20 C for an additional 4 hours and 16 minutes. The resultant slurry was quickly transferred to an electrically agitated HasteHoy filter dryer with 3-5 gm polypropylene filter cloth and the slurry was filtered under vacuum.
106501 The cake was washed with absolute ethanol (23.02 kg, x 3) and IPC
criterion required to be met. The wet cake was subsequently dried under vacuum with a jacket temperature of 65 C (allowed temperature range: 60 C to 70 C) for 29 hours and 59 minutes, until total volatiles (by moisture analyzer) are not more than 1.0%
w/w. The dryer was subsequently cooled, and the cake was collected to afford Compound A
(13.08 kg, 89%). Release results are shown below in Table 47.
106511 Table 47: Release results for Compound A:
Test Name Specification Result Description Light yellow to greenish yellow aystals Conforms Identification (by IR) Conforms to ref. spectrum Conforms Identification (by HPLC) Retention time of the main peak in the sample Conforms solution is consistent with reference standard (Not more than 5%) Purity (by HPLC) Not less than 98.0% (area) 99.6% (area) Related Substances (by UPLC) Not more than 0.15%
(area) Not detected Impurity 2 Related Substances (by UPLC) Not more than 0.13%
(area) Less than 0.05% (area) Impurity 3 Related Substances (by UPLC) Not more than 0.15%
(area) Not detected Impurity 4 Related Substances (by UPLC) Not more than 0.35%
(area) 0.12% (area) impurity at RRT ¨1.64 Related Substances (by UPLC) Not more than 0.13%
(area) 0.11% (area) Major unspecified impurity Related Substances (by UPLC) Report result by RRT in A (area) RRT 0.39: 0.11% (area) Any individual unspecified RRT 0.41:0.05% (area) impurity RRT 0.46: 0.06% (area) RRT 0.50:0.05% (area) RRT 0.56: 0.09% (area) RRT (0.06, 0.33, 0.48, 0.64, 0.65, 0.68, 1.12 and 1.17): Less than 0.05% (area) Test Name Specification Result Residual Solvents (by GC) Not more than 10000 ppm 5962 ppm Ethanol Residual Solvents (by (IC) Not more man 410 ppm Less than 123 ppm Acetonirtile Residual Solvents (by GC) Not more man 5000 ppm Not detected Acetone Residual Solvents (by GC) Not more man 5000 ppm Not detected Isopropyl Alcohol Residual Solvents (by GC) Not more than 720 ppm Not detected Tetrahydroftuun Residual Solvents (by GC) Not more than 5000 ppm Less than 1500 ppm Isopropyl Acetate Residual Solvents (by GC) Not more than 5000 ppm Not detected n-fieptatre Residual Solvents (by GC) Not more than 1000 ppm Not detected 4-Methylmotpholine Residual Solvents (by GC) Not more than 1000 ppm Not detected Dlisopmpylethylattrine Residual Solvents (by GC) Not more than 1090 ppm Less than 327 ppm N-N,Dimethylacetattride Residual Solvents (by GC) Report result Less than 900 ppm Methanol Residual Solvents (by GC) Report result Less than 180 ppm Dichloromethatie Water content (by KF- Oven) Report result Less than 0.5 % (w/w) Residue on ignition Report result 0,0 % (w/w) Particle size d(0.1) Report result 3 tun Particle size d(0.5) Report result 12 pin Particle size d(0.9) Report result 33 um X-ray powder diffraction Report result Crystalline Content of (by IIPLC) Acetic Report result Not detected Acid Differential scanning Report result (Onset and endot berm Onset temperature: 289.85 C
calorimetry (DSC) temperatures) Endotherm temperature:
293.68 C
FIFTH GENERATION SYNTHESIS
Example 26: Fifth Generation Synthesis of Compound A

106521 The fifth generation sequence followed the same general scheme as the fourth generation sequence. The steps of the fifth generation sequence are shown below. Material quantities are normalized to a hypothetical 1 kg starting material for each step. The quantities of starting materials are adjusted for potency according to the following formulae:
106531 Step 1:
106541 Reaction is performed under N2.
106551 Potency Calculations to Determine input (per Kg) of Intermediate 10 and Intermediate 7 Intermediate 7 potency = (100% - Loss on Drying%) x Purity = a wt.%
Intermediate 7 corrected target calculation = Intermediate 7: 1.00 kg x 11.0/(Intermediate 7(% w1w)1100)1 Intermediate 10 potency = (100% - (Loss on Drying% + Residue on Ignition%)) x Purity = b wt.%
Intermediate 10 corrected target calculation = 1.00 kg x 10.843/(Intermediate Potency(%w/w)/100)1 1. To Reactor A, add Intermediate 7(1.000 Kg 1.0%, corrected for potency as described above), Intermediate 10 (0.843 Kg 1.0%), HOPO (0.0580 Kg 1.0%, corrected for potency as described above).
2. To Reactor A add DMAc (2.82 Kg; or 3.0 L 5.0%) by spray ball.
3. Purge with N2.
4. Cool to 10 5 "C.
5. To Reactor A add DIPEA (0.495 Kg, or 0.669 L 1.0%) at 10 5 C.
Note: slightly exothermic, control addition to maintain temperature range.
6. Rinse line with DMAc (0.09 Kg or 0.10 L 5.0%).
7. Adjust to 10 5 'C.
8. Stir at 10 5 C for NLT 0.5 h.
9. To Reactor A add EDAC (0.701 Kg 1.0 %).
10. Chase with additional DMAc (0.66 Kg or 0.70 L 5.0%) via spray ball if necessary 1 1 . Adjust to 20 10 "C.
12. Stir at 20 5 'C.
13. After NLT 20 hrs, sample for IPC-1.
Note: 1PC < 1.0 AP residual Intermediate 7;
14. To Reactor B add NaC1 (1.00 Kg 5.0 %).
15. To Reactor B add tap water (6.6 Kg, or 6.6 L 5.0 %).

16. Stir at 25 5 C until a solution is formed.

17. Transfer contents of Reactor B to Reactor A

18. To Reactor A add tetrahydrofuran (5.34 Kg or 6.0 L 5.0%).

19. Adjust the internal temperature to 50 5 C.

20. Stir at 50 5 C for NLT 0.5 h.

21. Transfer the mixture from Reactor A through a Celite bed to Reactor B.

22. Wash Reactor A and the Celite bed with Tetrahydrofumn (1.34 Kg or 1.5 L
5%) and transfer to Reactor B.

23. Adjust contents of Reactor B to 50 5 C

24. Stop agitation and hold for NLT 1 hr.

25. Separate out the bottom aqueous layer.

26. To Reactor A add Sodium Chloride (1.25 Kg 5.0%).

27. To Reactor A add tap Water (6.60 Kg or 6.6 L/Kg 5.0%).

28. Agitate Reactor A for NLT 0.5 h. at 25 C until a solution is formed.

29. Transfer contents of Reactor A to Reactor B.

30. Adjust contents of Reactor B to 50 5 C

31. Stop agitation and hold for NLT 1 h.

32. Separate out the bottom aqueous layer from Reactor B.

33. To Reactor A add sodium chloride (1.50 Kg 5.0%).

34. To Reactor A add tap water (6.60 Kg or 6.6 L/Kg 5.0%).

35. Agitate Reactor A for NLT 0.5 h. at 25 C until a solution is formed

36. Transfer contents of Reactor A to Reactor B.

37. Adjust contents of Reactor B to 50 5 C

38. Stop agitation and hold for NLT 1 h.

39. Separate out the bottom aqueous layer from Reactor B.

40. To Reactor B add tetrahydrofiiran (7.57 Kg or 8.5 L 5.0%).

41. Heat contents of Reactor B to 65 5 C

42. Distill contents of Reactor B under atmospheric pressure at 65 5 "C with slight vacuum bleed (scrubber) until the volume is 3.30 L/Kg ( 0.5 L).

43. To Reactor B add tetrahydrofuran (7.57 Kg or 8.5 L :-/: 5.0%).

44. Heat contents of Reactor B to 65 5 C

45. Distill contents of Reactor B under atmospheric pressure at 65 5 C with slight vacuum bleed (scrubber) until the volume is 3.30 L/Kg ( 0.5 L).

46. Clean Reactor A with water and Tetrahydrofuran.

47. To Reactor A add Tetrahydrofuran (4.45 Kg or 5.0 L 5.0%).

48. Heat contents of Reactor A to 65 5 C.

49. Transfer contents of Reactor A to Reactor B via spray ball

50. Transfer contents of Reactor B to Reactor A via an in-line filter.

51.Rinse contents of Reactor B with Tetrahydrofuran (1.34 Kg or 1.5 L 5.0%) via spray ball and transfer to Reactor A via in-line filter.

52. Adjust contents of Reactor A to 65 5 'C.

53. Clean Reactor B with water and THF.

54. Distill contents of Reactor A under atmospheric pressure at 65 5 C with slight vacuum bleed (scrubber) until the volume is 6.0 L/Kg ( 0.5 L).

55. To Reactor B charge THF (1.34 Kg, 1.5 L 5.0%).

56. Heat contents of Reactor B to 65 5 C.

57. Transfer contents of Reactor B to Reactor A via spray ball.

58. Take sample for Water content (KF coulometric).

59. If result is 50.50 wt.% then continue to Step 62, if not continue to Step

60.
60. To Reactor A charge THF via spray ball (4.45 Kg or 5.0 L 5.0%).

61. Continue to Step 54.

62. Verify solution is present, increase agitation to help dissolve any solids on walls of reactor that are above solution.

63. To Reactor A charge n-Heptane (0.68 Kg, or 1.0 L 5%) at 65 5 C.

64. Charge a slurry of Intermediate 2 seed or Intermediate 2 (0.002 Kg) in n-Heptane (0.034 Kg or 0.05 L).

65. Stir at 65 5 C for 1 hr ( 30 minutes).

66. To Reactor A charge n-Heptane (2.72 Kg, or 4.0 L 5%) at 65 5 C over 3 hrs ( 30 minutes).

67. Stir at 65 5 C for 1 hr ( 30 minutes).

68. Cool down to 20 . 5 C over 3 hrs ( 60 minutes).

69. Stir at 20 5 C for 6 hrs ( 60 minutes).

70. Filter the slurry under vacuum at 20 5 C and de-liquor the cake.

71. Verify solids from Reactor A have been transferred to filter dryer.

72. Clean Reactor B with Water and Tetrahydrofuran.

73. To a Reactor B add Tetrahydrofuran (1.34 Kg or 1.5 L/Kg).

74. To a Reactor B add n-Heptane (0.68 Kg or 1.0 L/Kg).

75. Stir contents of Reactor B for 5 minutes at 20 5 C.

76. Transfer contents of Reactor B via spray ball to Reactor A.

77. Transfer contents of Reactor A to filter dryer and then re-slurry the cake for NLT
minutes.

78. De-liquor the cake under vacuum and nitrogen.

79. Dry the wet cake at 580 C (filter dryer jacket temperature) under vacuum until LOD passes (NLT 6 hrs).
LOD spec. = < 1.0% /120 C

80.The expected yield of Intermediate 2 = 1.44 Kg (88 mol% yield).
106561 Step 2:
10657] Reaction is performed under N2.
1. To Reactor A add Intermediate 2 (1.00 Kg 1.0%), NaBr (0.219 Kg 1.0%), and Na1-ICO3 (0.3575 Kg 1.0%) and NaC1 (1.80 kg 1.0%).
2. To Reactor A add TEMPO (3.325 g 1.0%).
3. To Reactor A add DCM (19.0 L 5.0%).
4. Chase TEMPO addition with DCM (0.50 L 5.0%) and add the solution to Reactor A.
5. Stir at 20 C for 0.5 h.
6. To Reactor A add deionized 1120 (7.0 L 5.0%).
7. To Reactor A add IPA (0.127 Kg 1.0%).

8. Chase IPA addition with DCM (0.50 L 5.0%) and add the solution to Reactor A.
9. Stir at 20 C for NLT 2.0 h.
10. Cool the mixture to -12 to -10 C, preferably to -11 C.
Note: maximum cooling control of the batch temperature is critical for this step;
11. To Reactor A add aq. NaCIO (1.15 eq 1.0%) by Spray Ball in NLT 15 min but NMT 45 min, preferably in < 0.5 h, while controlling the internal temperature between -12 to -3 C, preferably -12 to -8 "C.
Note: Mass of aq. NaC10 (Kg) = (1.15x 74.44)1(469.97 x Conc of aq. NaCIO
(wt%)) Note: the bleach solution is pre-cooled to 0 5 'C.
12. Chase the line with additional deioni zed 1120 (0.50 L :-/: 5.0%) by Spray Ball in NLT 5 min but NMT 0.5 h.
13. Stir at -12 to -3 C.; for NLT 1.0 h.
14. Sample the organic layer for IPC-1 analysis.
15. If1PC-1 fails, kicker charge of aq NaC10 (pre-cooled to 0 5 C) by Spray Ball in NLT 15 min but .Nm-r 45 min, preferably in <0.5 h, while controlling the internal temperature between -12 to -3 C, preferably - 12 to -8 C.
16. Chase the line with additional deionized H20 (0.50 L 5.0%) by Spray ball in NLT 5 min but NMT 0.5 h.
17. Stir at -12 to -3 C for NLT 1.0 h 18. Sample for 1PC-1.
19. If IPC-1 passes, adjust to 20 5 C.
21. Separate the bottom DCM layer in Reactor A to Reactor B.
Approximate volume of organic DCM phase (20 L/Kg) and solution is colorless to brown soln.
Approximate volume of aqueous phase is (10 L/Kg) and solution is colorless to light brown.
22. Remove aqueous phase from Reactor A and send to waste.
23. Clean Reactor A with Water, THF.
24. To Reactor B charge H20 (7.0 L/Kg 5.0%).

25. Stir Reactor B for NCI' 0.5 h at 20 5 "C.
26. Filter the mixture through a Celite bag to Reactor A.
27. Chase wash Reactor B with DCM (2.0 L/Kg) to Reactor A.
28. Wash Reactor B with H20 and THF.
29. Stop agitation of Reactor A for NLT 2.0 h.
30. Separate the bottom organic layer to Reactor B.
Note: Sample the DCM layer for UPLC analysis;
31. Distill the organic solution in Reactor B to volume = 5.0 L/Kg (+/- 0.5 vol) under normal atmosphere and batch temperature = 40 5 C
32. To Reactor B charge TI-IF (1.0 L/Kg 5.0%) by spray ball.
33. Adjust the batch temperature to 38 2 *C.
34. Add 5.0 L/Kg of n-Heptane over 0.5 h maintaining the batch temperature of 2 C.
35. Add Intermediate 3 seeds (5.0 g/Kg) in n-Heptane (0.10 L/Kg).
36. Stir at 38 2 C for NLT 4.0 h.
37. Add additional 5.0 L/Kg of n-Heptane over 1.0 h.
38. Stir at 38 2 C for NLT 2.0 h.
39. Cool down to 20 5 C over NLT 4 h.
40. Stir at 20 5 "C for additional NLT 6 h.
41. Filter the slurry under vacuum at 20 C and nitrogen.
42. If solids remain in the reactor, recirculate mother liquors back into reactor through spray ball and filter mixture again.
43. Wash Reactor B with 1..5 L/Kg of n-Heptane by spray ball.
44. Slurry wash the cake and remove liquors under vacuum until most of liquors are removed.
45. Remove liquors under vacuum and pull until most of liquors are removed.
46. Dry the cake at NMT 50 C 5 C for NLT 8 h under vacuum and nitrogen.
47. Continue drying the cake at 75 5 "C under vacuum and nitrogen flow until LOD
< 1.0%/120 C.
48. Expected Intermediate 3 amount 0.95 Kg (95 mol%).

106581 Step 3:
106591 Potency Calculations to Determine input (per Kg) of Intermediate 3 and Intermediate 5 Intermediate 3 potency calculation = (100% - Loss on Drying%) x Purity = a wt.%
Intermediate 3 corrected target calculation:
Intermediate 5: 1.00 Kg x (1.0/(Intermediate 3 Potency(% w/w)/100)) Intermediate 5 potency calculation = (100% - (Water Content% + Residual Solvents%)) x Purity b wt.%
Note: Water Content, Residual Solvents, and Purity data obtained from Intermediate 5 CofA
Intermediate 5 corrected target calculation:
Intermediate 5: 1.00 Kg x (0.848/(overall potency /100)) 1. To Reactor A, charge NaBH(OAc)3 (0.679 Kg 1.0%).
2. To Reactor A, charge DMAc-1 (2.75 vol 5%).
3. Once dissolved, hold Reactor A at 20 _+_ 5 C, for NLT 1.0 h 4. To Reactor B, charge Intermediate 5 [0.848 / (b wt.%/100)] Kg) 1.0%), Intermediate 3 (1.000 / (a wt.%/100) Kg 1.0%) and DMAc-2 (4.90 vol 5%).
5. Cool Reactor B to 0 5 'C.
6. To Reactor B, charge .W-Methylmorpholine (0.540 Kg 1.0%) in NLT
0.5 h while keeping the batch temperature at 0 5 'C.
7. Agitate Reactor B at 0 5 C for NLT 2.0 h but NMT 4.0 h.
8. Transfer the contents in Reactor A to Reactor B over NLT 1.0 h, while maintaining internal temperature at 0 5 C.
9. Rinse Reactor A with DMAc-4 (0.64 vol 5%) and transfer to Reactor B
in NLT 15 min.
10. Agitate Reactor B at 0 5 C for NLT 6.0 h.
11. Sample for IPC-1.
IPC-1 criteria: Intermediate 3 < 2.0%;
12. If IPC-1 fails, continue agitation at 0 5 C for an additional 6 b.

13. Sample again for IPC-1.
14. If IPC-1 fails again, check for technical advice.
15. To Reactor B, charge Et0H (6.2 vol 5%) over NLT 0.5 h while maintaining temperature at 0 5 C.
16. To Reactor B, charge H20 (6.2 vol 5%) over NLT 0.5 h while maintaining temperature at 0 5 C.
17. Adjust the content in Reactor B to 50 5 C in NMT 2.0 h.
18. Hold the content in Reactor B at 50 5 "C for NLT 1.0 h but NM'F 2.0 h.
19. Cool the content in Reactor B to 20 5 C in 3.0 h 0.5 h.
20. Hold the content in Reactor B at 20 5 C for NLT 4.0 0.5 h.
21. Transfer the slurry in Reactor B to Filter C (filter cloth = 3-5 pm) under N2 blanket and filter.
22. Wash Reactor B by spray ball with Et0H (1.75 vol 5%) and H20 (1.75 vol 5%) at 20 5 C.
23. Filter the content in Reactor B (re-slurry) under N2 blanket.
24. Wash the wet cake (re-slurry) with Et01-1/1-120 (1:1; 3.5 vol 5%) at SOC.
25. After de-liquoring washes, continue to de-liquor the wet cake for NLT 2 hrs and until no major solvent is removed from the filter drier.
26. Perform four slurry washes of the wet cake in Filter C with Et0H (4 x 3.5 vol - 5%).
27. De-liquor the wet cake in Filter C for NLT 1 h after each of the four slurry washes.
28. Sample the wet cake in Filter C for IPC-2 (LOD (2 g, 120 C)) and perform the calculation:
Correction for Et0H in Compound A crude cake (97 mol% Compound Ah Intermediate 3 (Kg) input x 1.684 = Calculated Compound A crude product (Kg) Et0H in wet Compound A crude product (Kg) = LOD% x Calculated Compound A crude product (Kg) / (1-LOD%) (Et0H in wet Compound A crude product (Kg) / 0.789) / (Intermediate 3 (Kg) input) = Et0H content (vol) to be corrected Et01-1 content (w1) to be corrected Subtract from Et0H to be added in Step 38 (7 vol Et0H) *Charges based on initial Intermediate 3 input*
29. Charge DCM (28.0 vol 5% of Intermediate 3) to Reactor A.
30. Charge Me0H (2.8 vol 5% of Intermediate 3) to Reactor A and agitate for NLT 0.5 h.
31. Transfer half of DCM/Me0H (10:1, 15.4 vol 20%) from Reactor A to Filter C.
32. Agitate Filter C at 20 5 C for NLT 0.5 h to dissolve most of the wet crude solids.
33. Polish filter the solution in Filter C to Reactor B via an in-line capsule filter.
34. Transfer part of the remaining DCM/Me0H (10:1, 14.4 vol 5%) from Reactor A to Filter C.
35. Agitate Filter C at 20 5 C for NLT 0.5 h to dissolve all of the remaining crude solids.
36. Polish filter the solution in Filter C to Reactor B via an in-line capsule filter.
37. Rinse Filter C with remaining DCM/MeOli (10:1; 1.0 vol 5%) and filter to Reactor B via an in-line capsule filter.
38. Distill the solution in Reactor B while maintaining a constant volume (vmax ¨32 vol) under atmospheric conditions with continuous addition of Et0H
(7.0 vol 5% vol Et0H from Step 28 calculation) at an internal temperature between 35-45 C.
39. Sample for IPC-3, GC analysis for DCM content.
IPC-3 criteria: DCM 67 vol % (relative to total volume of DCM+Me0H-1-Et0H

peaks);
Report Et0H vol % and Me0H vol %.
40. If DCM content is passing, go directly to Step 43. [fit is failing, go to Step 41. If IPC-3 fails, continue distillation with additional Et0H (1.0 vol -5%) and re-sample for GC analysis IPC-3 criteria: DCM 67% (relative to total volume of DCM-I-Me01-1-i-Et0H
peaks);
Report Et0H vol % and Me0H vol %.
42. If IPC-3 fails again, repeat Step 41.
43. Cool Reactor B to 35 2 C and charge Compound A seeds (0.50 wt%
5%) in Et01-1 (0.075 vol 5%).
44. Agitate Reactor B at 35 2 C for NLT 0.5 h 45. Heat Reactor B back up to reflux conditions (41 2 C) and continue constant volume distillation (vmax -32 vol) under atmospheric conditions with the continuous addition of Et0H (7.0 vol 5%) while maintaining batch temperature between 40-50 'C.
46. Continue distillation in Reactor B under constant volume (vmax -32 vol) under atmospheric conditions until the internal temperature reaches at least 50 'C.
47. Perform remainder of distillation in Reactor B under vacuum maintaining a constant volume (vmax -32 vol) with addition of Et0H (28.0 vol . 5%) and maintaining internal temperature at 55 10 C.
48. Sample Reactor B for IPC-4 by GC.
IPC-4 criteria: DCM/Et0H < 1.0%.
49. If IPC-4 fails, repeat the vacuum distillation with additional Et0H
(4.0 vol 5%) and continue to step 50.
50. Sample Reactor B for IPC-4 by GC.
IPC-4 criteria: DCM/Et0H < 1.0%.
51. If1PC-4 passes, adjust the batch temperature to 55 5 'C.
52. Agitate the slurry in Reactor B at 55 5 C for NLT 0.5 h.
53. Cool the slurry in Reactor B down to 20 5 C in NLT 3.0 h.

54. Agitate the slurry in Reactor B at 20 5 C for NLT 4.0 h.
55. Filter the slurry in Reactor B to Filter C (filter cloth = 8 gm).
56. Rinse Reactor B with Et0H (3.5 vol 5%).
Note: Et0H should be polish filtered.
57. Filter the rinse in Reactor B and transfer to Filter C as a slurry wash.
58. Perform two slurry washes of the wet cake in Filter C with Et0H (2 x 3.5 vol 5%).
Note: Et0H should be polish filtered.
59. De-liquor the cake in Filter C for NLT 1 h 60. Sample Filter C for IPC-5 for the impurity profile of the wet cake.
Unspecified 1PC-5 Specified Impurities Individual Compound A
Impurity Itnpurity impurity 2 Impurity 3 Impurity 4 RRT 1.64 Any' Criteria (%) <0.15 -11.13 -11.15 <0.35 <0.13 NLT
98.0%
61. If1PC-5 fails, go back to step 28 (Sample wet cake for LOD, perform Et0H Calculation and start the distillation).
62. If IPC-5 passes, dry the cake under vacuum with agitation at 80 5 C.
Note: sample the wet cake for PDXR, DSC and KF (FI0).
63. Sample contents in Filter C for IPC-6, LOD (2 g,120 C) IPC-6 criteria: LOD (2 g,120 C) < 1.0% after NLT 8 h.
64. If IPC-6 fails, continue drying until LOD criteria is met.
65. If1PC-6 passes, sample for 1PC-7 (GC analysis).
66. 1PC-7 criteria: GC residual solvents ACN Acetone WA Et011 THF iPAc Heptane NMM DWEA DMA
Solvent NMT NMT NMT NMT NMT NMT NMT NMT NMT NMT
PPm 67. If IPC-7 fails, continue drying until GC criteria is met.
68. Once IPC-7 passes, discharge the material from Filter C.
106601 The fifth generation process described above was conducted on a 1.7 kg scale (relative to Intermediate 3), to afford Compound A (2.420 kg). Purity was calculated to be 99.9% by UPLC (see FIG. 26 and Table 48).

Table 48: Peak Results for Chromatogram of Purified Compound A
Name RT RRT Area % Arc a USP Resolution USP
Tailing 1 Intermediate 5 1.361 2 Intermediate 7 5.252 3 impurity 1 6.374 4 Impuriay at RT ¨7.78 '7.782 impurity at RT ¨"/.95 7.949 6 Intermediate 3Accial 8.379 7 Diacid (wittily 8,594 8 impurity a RT -,8.78 8,784 9 impurity a RT -,9.72 9,715 Intermediate 2 10.169 II Intermediate SiNiethyl 11.219 Hcmiacetal 12 fine [nictitate 3 13.057 13 Ring 2 Methanoly sis 16.232 Adduct-1 14 Ring 2 Mcittannlysis 18.381 Adduct-2 Impurity 2 19.097 16 Impurity 3 20.529 17 impurity at RI ¨21.77 21.770 18 impurity 4 22176 19 Compound A 23.871 1.00 3784159 99.854 0.9 impurity at RI ¨24.18 24.181 21 impurity at RI ¨24.90 24.897 22 Carbamatc Imputity 26.735 23 finpurny at RRT ¨1.64 39.1.01 [64 5527 0,146 .. 38.8 ..
2.3 Stun 3789585 106611 Example 27: Development of High-Strength Compound A Tablet 10662j Due to a demand for a higher strength tablet for Phase I dose escalation trials, a higher strength tablet was developed, 106631 The higher strength tablet formulation was accomplished in two phases.
The first phase screened the loading of the 100% amorphous spray dried API (SDI) in the tablet formulation using miniaturized laboratory techniques, and the second phase optimized the selected formulation composition.

106641 The formulation compositions during the screening phase encompassed a range of SDI loads equal to 10% to 40%, and tablet strengths equal to 70 mg, 140 mg, and 280 mg (for 700 mg Tablet Press Weight), as outlined in Table 49 Table 49: Formulation compositions of higher strength SDI loads ¨ 10%, 20% and 40% (700 mg Tablet Press Weight) Formulation Reference Cl C2 C3 Tablet Strength; Tablet Press Weight (mg/mg) 70/700 140/700 280/700 Function Ingredient % of Blend Intra Granular Active Spray-dried amorphous Compound A 10.00 20.00 40.00 Filler Microaystalline cellulose 57.33 50.67 37.33 Filer Lactose monolwdrate 28.67 25.33 18.67 Disintegrant Croscannellose sodium 3.00 3.00 3.00 Glidant Silicon dioxide 0.50 0.50 0.50 Lubricant Magnesium stearate 0.25 0.25 0.25 Extra Granular Lubricant Magnesium stearate 0.25 0.25 0.25 Totals: 100.00 100.00 100.00 106651 Tablets were made using a miniaturized laboratory technique to simulate dry granulation and compression. The pregranulation blend was slugged on an F-press. The slugs were size reduced using a mortar/pestle, and passed through a 20-mesh sieve for proper sizing. The granules were mixed with magnesium stearate and compressed on an F-press.
106661 After selecting a tablet tensile strength to achieve a sufficiently hard tablet with disintegration time of less than 5 minutes, the tablet in vitro performance of each tablet composition (Cl, C2 and C3) was evaluated using a USP sink dissolution test.
As a benchmark, the 10-40% SDI loaded tablets were compared against the original 5%
SDI
loaded tablets (Tablet reference A3, above).
106671 Dissolution method TEST-1973: To maintain equivalent sink conditions that enabled a valid comparison between formulations, the dissolution media consisted of 0.01N HCl with 0.1 wt% Tween 80. Using USP compatible vessels, the volume of the media was adjusted for each tablet strength to maintain a constant sink condition (approximately 4 x). The dissolution parameters are USP II paddles, 37.0 0.5 C media temperature, 75 RPM and sampling times equal to 10, 15, 20, 30, 45 and 60 minutes. The dissolution results are shown in FIG. 27. The data for each composition was normalized to the 90 minute time point to compensate for variability in the potency and permit a more valid comparison. The dissolution extent for all compositions was equivalent at 60 minutes. The 20% load tablet provided sufficient tablet strength for intended use.
106681 Since the goal was to maximize the SDI loading, the 20% formulation composition was systematically modified with the aim of increasing the dissolution rate.
Refer to Table 50 for a listing of the 20% SDI loaded compositions. These formulations were prepared using the miniaturized laboratory techniques described above for the 10, 20 and 40%
compositions. The rationale of the modifications is a more rapid de-aggregation phase of the disintegration/dissolution mechanism. The changes are summarized below:
= Di- smaller microcrystalline cellulose to enhance the association with the micron sized SDI particles and therefore enhance disintegration = D2 --- addition of extra-granular disintegrant to reduce the time for the primary SDI particles to be exposed to the dissolution medium = D3 --- addition of smaller size glidant to aid in the more intimate association with the SDI particles and therefore favor the physical separation of the SDI
particles in the formulation = D4 ¨ similar to D2, increased the total level of the disintegrant to favor a faster disintegration time Table 50: Formulation compositions of 20% SDI loaded higher strength tablet compositions (700 mg Tablet Press Weight) Formulation Reference DI D 2 1)3 1)4 Tablet Strength/ Tablet Press Weight (mg/mg) 140/700 140,700 140/700 140:700 Function Ingredient 14, of Blend intra Granular Active Spray-dried amorphous Compound A 20.00 20.00 20.00 20.00 Filler Microcrystalline cellulose (Avicel PH 102) 49.33 50.33 46.00 Filler Miciociystalline cellulose (Avicel PH to 76.00 Filler Lactose monohydrate 24.67 25.17 23.00 Disintegrant Croscarmellose sodium 3.00 3.00 3.00 6.00 Glidant Silicon dioxide (Syloid 244 FP) 0.50 0.50 0.50 GI:Want Silicon dioxide (Cab-O-Sil M5P) 1.00 Formulation Reference 1)1 1)2 1)3 1)4 Tablet Strength/ Tablet Press Weight (mg/mg) 140/700 140,700 140,700 140,700 Function Ingredient % of Blend Lubricant Magnesium stearate 0.25 0.25 0.25 0.25 Extra Granular Disintegrant Crosearmellose sodium 2.00 4.00 Lubricant Magnesium stearate 0.25 0.25 0.15 0.25 Totals: 100.00 100.00 100.00 100.00 106691 Overall, the formulations processed similarly except for flowability of D1 and all of them exhibited disintegration times in 0.01 N HCl of less than 1 minute;
therefore, a major selection criterion for further evaluation was the dissolution characteristics.
Dissolution profiles using the 0.01 N HO media method (TEST-1973) for D1, D2, D3, D4 and 35 mg (5%) are illustrated in FIG. 28.
106701 The scale up and process evaluation of the D2 formulation was conducted to identify the processing conditions to be used for the planned clinical manufacture. The batch size was approximately 3 kg and consisted of the following major steps:
= Pre-granulation blend using the 100% spray-dried intermediate of Compound A
= Roller compaction (Gerteis Minipactor machine) = Final blend (addition of extra-granular disintegrant and lubrication) = Compression (Korsch XM:12) 106711 The flow properties of the pre-granulation blend and final blend were determined using laboratory techniques (Carr Index, shear cell flow function/cohesion coefficient and FloDex measurements), roller compaction parameters determined and a compression evaluation (compressibility, tabletabilty and compactability) was conducted.
106721 During the compression of the final blend on the Korsch XM-12 equipped with 2 tool stations to accommodate the batch size, the granulation exhibited insufficient flow.
The material rat-holed and bridged in the feed hopper, starving the feed frame, and thus, resulted in poor weight control.
106731 Due to the flow challenges, it was determined that the D2 formulation and process were not suitable and therefore, not transferrable for clinical manufacture.
As a result, another round of formulations was evaluated in the laboratory to improve flowability characteristics.

106741 The modification strategy for the D2 formulation hinged on evaluation of the glidant system being used and optimized its functionality. Two new formulations, F7 and Fll are shown in Table 51.
Table 51: D2, F7 and F11 Formulation compositions of 20% SDI loaded tablet (525 mg Tablet Press Weight) Formulation Reference D2 P7 F11 Tablet Strength/ Tablet Press Weight (mg/mg) 105,525 105/525 105/525 Function Ingredient % of Blend Int ra Granular Active Spray-dried amorphous Compound A 20.00 20.00 20.00 Filler Microcrystalline cellulose (Avicel PH 102) 49.33 48.17 49.00 Filler Lactose monohydrate 24.67 24.33 24.50 Disintegrant Croscarmellose sodium 3.00 3.00 3.00 Glidant Silicon dioxide (Syloid 244 FP) 0.50 Glidant Silicon dioxide (Cab-O-Sil M5P) 1.00 0.50 Lubricant Magnesium steanite 0.25 0.25 0.25 Extra Granular Glidant Silicon dioxide (Cab-O-Sil MW) 1.00 0.25 Disintcgrant Croscarmellose sodium 2.00 2.00 2.00 Lubricant Magnesium stearate 0.25 0.25 0.50 Totals: 100.00 100.00 100.00 106751 The F7 and Fll compositions were manufactured at bench scale (50g per blend) at a Tablet Press Weight of 105 mg using the miniaturization techniques described above for formulations C1.-C3. The lower Tablet Press Weight was chosen to represent the midpoint of a range of Tablet Press Weights that may be needed for further dose escalation. Both formulations implemented an initial SDI/glidant blend-mill-blend process as part of the pre-granulation blend manufacture in an attempt to adhere to the SDI particles and reduce their cohesivity. Formulation F7 increased the overall glidant levels (intra-and extra-granular) and formulation Fl1 added glidant extra-granular and also increased extra-granular lubricant to assess if increased extra-granular glidant and lubricant had a synergistic effect on blend flow.
106761 The flowability of F7 and Fl 1 was compared to D2. Table 52 shows a modest improvement in the flowability (FloDex, FT`c and Cohesion Coefficient) for the final blend for both F7 and Fll compositions however, Carr Index remained at an unacceptable value.

106771 Scanning electron microscopic analysis showed minimal adherence of Cab-O-Sil to SDI particles, and miniscule to no surface coverage of SDI particles with Cab-O-Sil.
Table 52: Compound A Formulation D2, F7 and Fli Pre-granulation and Final Blend Flow Properties Formulation D2A Formulation F7 Formulation F!!
Pre- Pre- Pre-Final Final Parameter granulation Blend granulation Final Blend granulation Blend Blend Blend Blend Bulk Density 0.42 0.50 0.36D 0.443 0.39D 0.48B
(gin114 Tapped Density 0.63 0.70 0.59D 0.63D 0.63D 0.60 (g/mI) Carr Index (%) 34 28 39 30 38 31 FloDex (mm) 24 30 26 20 24 22 FFcc 4.9 5.1 5.9 7.6 4.7 6.1 Cohesion Coefficient') A Values from scale up manufacture. Blend not remanufactuxed at bench scale.
B Generated using 10m1., cylinder due to limited material. Results less reliable than those generated using 100mL cylinder.
cF.Fc is the shear cell flow function DCohesion coefficient was derived horn the shear cell data 106781 Tablet compression evaluation of F7 and Fl 1 showed similar results with D2 and confirmed no significant adverse impact of changing the glidant system. The formulations formed acceptable tablets at relatively low range compression stress (75 to 100 MPa), and both formulations exhibited disintegration times of less than 1 minute.
106791 Dissolution characteristics of F7 and F 11 were similar to 1)2 demonstrating no adverse effect of new glidant system on the dissolution properties.
106801 In conclusion, the modest improvement in flowability of F7 and Fll compared to D2 was not sufficient to nominate either one of them as the clinical formulation candidate, therefore, further formulation optimization was undertaken.
106811 Since the additional step of pre-mixing glidant with SDI did not produce a desirable outcome, this approach was abandoned. However, the unexpected result of almost no adhesion of the glidant to the SDI formed the basis of evaluating a chemically modified formed of colloidal silicon dioxide to increase its hydrophobicity and lower its surface free energy.

106821 A direct comparison of Cab-O-Sil M5P and A.erosil R972 was carried out.
As mentioned above, Aerosil R972 is colloidal silicon dioxide chemically modified to produce trimethylsilyl groups on the surface. It complies with USP/NF monograph for colloidal silicon dioxide. In this comparison, each of these glidants was added to the D2 blend from the scale up batch to directly study their impact on flowability compared to D2. The formulation compositions are listed in Table 53.
Table 53: Compound A - 61* and G2* formulation compositions Formulation Reference G1* G2*
Dose/Tablet Press Weight (mg/mg) 105/5303 Function Ingredient % of Blend Active 200mg/g Compound A Formulation D2 Final Blend 99.00% 99.00%
GI idant Silicon Dioxide (Cab-O-Sil M5P) 1.00%
Glidant Silicon Dioxide (Aerosil R972) 1.00%
Total 100.00% 100.00%
106831 The flow metrics are listed in Table 55. G2* exhibited the best flow properties compared to D2 and GI*.
Table 54: Compound A Formulations D2, Gi* and G2* Final Blend Flow Properties Formulat Formulation Formulation D2A
Pre- 61* 62*
Parameter granulation Final Blend Final Blend Final Blend Blend Bulk Density (g/mL) 0.42 0.50 0.49 0.54 Tapped Density (g/mL) 0.63 0.70 0.65 0.69 Carr Index (%) 34 28 25 22 FloDex (mm) 243 30B 26 14 Ffcc 4.9 5.1 6.2 8.0 Cohesion Coefficient 103 103 81 64 A Values from scale up manufacture. Blend not remanufactured at bench scale.
B Scale-up blend samples retested using the same fill levels as used for formulation Gl* and G2* blends.
eFFc is the shear cell flow function Cohesion coefficient was derived from the shear cell data 106841 The compressibility (solid vs compression stress), tabletability (tablet tensile strength vs compression stress) and compactability (tablet tensile strength vs tablet solid fraction) i.e. CTC profiles, for GI and G2 were compared. Formulation GI had similar CTC properties to formulation D2 suggesting Cab-O-Sil had minimal impact on the final blend material properties. Formulation G2 showed an improvement in compressibility but a reduction in both tabletability and compactability properties compared to both formulations G1 and D2. The significance of this finding was eventually assessed at larger scale and rotary press. The compressive stress regime for both G formulations was well within the typical range observed for optimal tooling wear performance and tablet porosity (100 to 300 MPa).
106851 A dissolution comparison of the bench-scale tablets of G1 and G2 demonstrated comparable dissolution profile, as shown in FIG. 29.
106861 Given G2 exhibited the best flowability, acceptable compression/tablet properties, and similar dissolution profile to D2, it was selected for further evaluation for a pre-demonstration processability assessment.
106871 A processability pre-demonstration assessment was conducted on a Gerteis Minipactor using bench scale batch size equal to 100 gram to determine target Gerteis settings for the demonstration batch. The Gerteis was set up with a feed funnel system designed to feed material quantities that are too small to use the auger feed and tamping systems. Ribbons were collected and then manually fed through the oscillating granulator to size them.
106881 The main purpose was to evaluate the effect of ribbon solid fraction on granule size.
106891 The G2 formulation composition is listed in Table 55. The composition differs slightly from the composition of G2* but was not expected to significantly impact granule or tablet properties. The tablet press weight was adjusted to 525 mg (vs 530 mg for G2*) and the Aerosil R972 quantity is exactly 1% of the composition.
Table 55: G2 formulation composition (20% SDI loaded tablet - 525 mg Tablet Press Weight) Formulation Reference G2 Tablet Strength/ Tablet Press Weight (mg/mg) 105'525 % of Function Ingredient Blend Int ra Granular Active Spray-dried amoiphous Compound A 20.00 Filler Microcrystalline cellulose (Avicel PH 102) 48.67 Filler Lactose monohydrate 24.33 Disintegrant Croscarmellose sodium 3.00 Glidant Silicon dioxide (Syloid 244 FP) 0.50 Lubricant Magnesium stearate 0.25 Extra Granular Formulation Reference G2 Tablet Strength/ Tablet Press Weight (mg/mg) 105/525 % of Function Ingredient Blend Glidant Silicon dioxide (Aerosil R972) 1.00 Disintegrant Croscartnellose sodium 2.00 Lubricant Magnesium stearate 0.25 Totals: 100.00 106901 The effect of adjusting the ribbon tensile strength on the granule size distribution and the effect of final blending on the granule size distribution is shown in FIGs. 30A and 30B. Granule size decreased as the ribbon tensile strength increased.
106911 The effect of ribbon tensile strength (granulator screen constant =
1.00 mm) on flow properties was also assessed and shown in Table 57. The flow metrics are better compared to the bench-scale trials, Carr Index = 21-23; FloDex = 16, and FFc = 7.1 ¨
8.5 are indicative of a free-flowing granulation.
Table 56: Pre-demo G2 composition final blend flow characteristics Parameter 1 2 3 Ribbon Tensile Strength (MPa) 1.10 0.60 0.77 Flow Characteristics Bulk Density (ging..) 0.60 0.55 0.51 Tapped Density (g/mL) 0.76 0.71 0.66 Carr Index (%) 21 23 22 FloDex (mm) 16 16 16 Flow Function, FTc 7.1 8.1 8.5 Cohesion Coefficient (Pa) 73 65 58 106921 CTC scans of tablets made on the F-press using G2 pre-demo batches are consistent with what was observed for the tablets manufactured using bench-scale equipment. The granulation is highly compressible and compactible and produces a tablet with acceptable tensile strength at compressive stresses in the range of 100 MPa. Noteworthy is a steep tensile strength vs. solid fraction, as noted previously. Higher solid fraction means lower tablet porosity. Tablet porosity is a known factor that can affect dissolution, therefore, the effect of tensile strength of tablets on dissolution rate and extent was also evaluated.
106931 The dissolution profiles of G2 pre-demo tablets compressed at 2.0 and 2.5 MPa are compared to the D2 tablets compressed at 2.5 MPa, as shown in FIG. 31. The dissolution profiles are similar, showing no discernable difference in dissolution profile as function of tablet porosity.
106941 In conclusion, based on improved flow behavior, acceptable tablet properties and acceptable tablet dissolution, the G2 tablet composition using Gerteis settings determined during the pre-demo laboratory-sized batches was selected for manufacture of a demonstration batch.
106951 Biopharmaceutical performance of 5% (A3) and 20% (G2) drug loaded tablets was assessed by orally dosing the corresponding tablets and comparing the plasma levels thereby obtained. 24 dogs were divided into two groups. Each group was fasted overnight and then fed regular chow 30 minutes before tablet administration followed by 30 mL of water. Otherwise, water was withheld from 1 hour before to 1 hour after dosing. 50 minutes before tablet dosing all subjected were pretreated with a 6 mg/ml, intramuscular pentagastrin solution. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose. One group was administered 2 of the 35 mg tablets containing a 5% load of Compound A and the other group was given 1 of the 70 mg tablets containing a 20% of Compound A.
106961 As shown in Table 57, similar exposure in pentagastrin pretreated, fed state dogs was observed when orally administered two of the 35 mg (5%) or one of the 70 mg (20%) tablets.
Table 57. Comparison of Oral Exposure Derived From Dosing Two 35 mg (5% Drug Load) orOne 70 mg (20% Drug Load) Tablet to Dogs Tablets AU CO-last (ngxh/m1-) Administered Avg SD
2x.35 mg 5,489 3,511 1/70 mg 5,481 4,404 106971 Example 28. Late Phase 1 Tablet Demonstration Batch Formulas [06981 A common granulation/bracketing strategy was applied for manufacturing the demonstration batch for the 20% SDI drug load formulation composition. The manufacture of tablets with a tablet press weight bracketed between 35 mg and 140 mg tablet strength (i.e. 175 mg to 700 mg tablet press weight) was implemented in the following manner. A
portion of a demonstration common granulation final blend was aliquoted to compress 35 mg, 70 mg and 140 mg tablets using a single-station compression machine. The remainder of the common granulation was used to compress a batch at 105 mg strength (525 mg tablet press weight) on a rotary tablet press, representative of the clinical manufacturing tablet machine. The 35 mg, 70 mg, 105 mg and 140 mg demonstration batches were used in the stability studies described in Example 29 below.
106991 The formulation compositions, granulation batch quantities and number of tablets are listed in Table 58.
Table 58: Demonstration Batch Formulae for Compound A Tablets, 35 mg, 70 mg, 105 mg and 140 mg Strengths Using 20% SDI Load.
Theoretical Quantity per Batch (p.) 35 mg 70 mg 105 mg 140 mg strength/ strength/ strength/ strength/
Ingredient 175 mg 350 mg 525 mg 700 mg Tablet Tablet Tablet Tablet Common Press i Press Press Press Granulation Weight 1 Weight Weight Weight Intra-granular 100% Compound A SDI 398.61 10.50 9.80 278.62 41.40 Microcrystalline cellulose 970.06 25.55 23.85 678.06 100.74 (Avicel pH102) Lactose monoliydrate 485.01 12.77 11.92 339.02 50.37 (FastFlo 316) .
Croscarinellose sodium 59.78 1.57 1.47 41.79 6.21 (Ac-Di-Sol) Silicon Dioxide 10.03 0.26 0.25 7.01 1.04 (Syloid-244) Magnesium stearate 5.01 0.13 0.12 3.50 0.52 Total 1ntra-granular 1928.5 50.79 47.41 1348.00 200.27 Extra-granular Croscamiellose sodium 39.87 1.05 . 0.98 27.87 4.14 (Ac-Di-Sol) Silicon Dioxide 19.93 0.53 0.49 13.93 2.07 (Aerosil R.972) Magnesium stearate 4.98 0.13 0.12 3.48 0.52 Total granulation 1993.28 53 49 1393.28 207 Total number of tablets 300 140 2654 296 Theoretical quantity per batch for the 105 mg tablet was calculated after samples taken for testing and manufacture of the 35 mg, 70 mg, and 140 mg tablet strengths Common granulation was divided to manufacture the 35 mg, 70 mg. 105 nig and 140 mg tablet strengths 107001 Prior to blending, Compound A drug substance is dissolved, then spray-dried to form an amorphous drug product intermediate as described above.

107011 The common granulation ribbons were manufactured to achieve an actual ribbon solid fraction = 0.60 that equates to an estimated tensile strength of 0.8 MPa.
107021 The final blend granule size distribution was reproducible, comparing favorably to the pre-demo batch, as depicted in FIG. 32.
[0703] The final blend flow metrics were also reproducible, comparing favorably to the pre-demo batch, shown in Table 59.
Table 59: Comparison of flow metrics between the pre-demonstration and demonstration final blend batches of G2 composition, granulated to a ribbon tensile strength of 0.811,1Pa.
Final Blend- Pre-demo Final Blend ¨ Demo Parameter Batch Batch Bulk Density (g/m1..) 0.51 0.55 Tapped Density (g/mL) 0.66 0.69 Carr Index (%) 22 20 FloDex (mm) 16 14 Flow Function, FFc 8.5 13.8 Cohesion Coefficient (Pa) 58 34 107041 The final blend was divided into 4 portions. Three portions of 100 gram each were used to manufacture the 35 mg, 70 mg and 140 mg tablets on the single-station machine, and the remainder (approximately 2 kg) was used to manufacture the 105 mg batch on a rotary tablet machine.
107051 The 35 mg, 70 mg and 140 mg tablet strengths were compressed to 2.0 MPa tensile strength round tablets. The tablet disintegration times were 2.3 to ¨3.0 minutes for the 140 mg, 1.5 to 2.0 minutes for the 70 mg and ¨1 to 1.3 minutes for the 35 mg tablet.
107061 The 105 mg demonstration batch exhibited good flow as evidenced by the excellent weight and hardness control and excellent uniformity of dosage units. Tablet press weights were easily maintained at the in-process limit for individual tablets of 5 %.
Uniformity of dosage units UPS <905> AV = 3.5, mean = 97.2 % label claim.
[0707] Comparison of the dissolution for 35 mg, 105 mg and 140 mg are shown in FIG.
33. The dissolution was performed for the tablet strengths that were used in stability studies, which bracketed the highest, lowest and mid-range strengths. The dissolution profiles are comparable, demonstrating no tablet strength effect on the dissolution rate and extent.
107081 In conclusion, based on acceptable processability and final product performance, the G2 composition was nominated for manufacture of clinical tablets that can be bracketed between 35 mg and 140 mg strengths Example 29: Stability of Formulation G2 Tablets 107091 Tablets of formulation G2 with strengths of 35 mg, 105 mg, and 140 mg Compound A were subjected to a stability study (Table 61).
1071.01 Protocol (Tablet Packaging) 107111 Packaging Supplies:
= White 500cc HDPE Pharma Round Bottles with HIS lids = ig Sorb-It desiccant canisters 107121 Tablet Packaging Protocol:
1. Add (22) tablets to a 500cc HDPE bottle.
2. Add (1) 1g Sorb-it desiccant canister to the HDPE bottle.
3. Place a HIS lid on the HDPE bottle and seal the bottle using an Enercon Super Seal Jr. cap sealer at 60% sealing power for one second.
4. Remove the bottle lid to ensure the foil seal is properly adhered to the bottle. Screw the cap back on the bottle before placing the bottle in the appropriate stability chamber.
Table 60: Tablet Stability Conditions, Time Points and Testing Condition 1 Month (1) 3 Month (2) 6 Month (3) 12 Month (4) (a) 5 C, closed with desiccant A A A A. B, C
(b) 25'060%RH, closed with desiccant A. B. C A. B. C A. B. C
A, B, C
(c) 40 C/75%R.14, closed with desiccant A, B. C A, B. C A. B. C

A ¨ 105mg Fommlation G2 B ¨ 140mg Fomiulation G2 C ¨ 35ing Formulation G2 107131 The tablets were analyzed for appearance, assay and related substances by UPLC, dissolution by USPII, and water content by volumetric KF. Based upon the characterization below, all of the tablet doses were as expected for appearance, assay, dissolution performance, and water content. The purity was slightly increased when compared with the SDI used for manufacture and should be monitored closely in subsequent stability pulls.
107141 The tablets were visually evaluated for appearance. All of the tablets were yellow, smooth surfaced tablets.
1071.51 Tablet assay values were consistent for each dose and met the current specification of 90% - 110% LC (Table 62).
Table 61: Tabulated Composite Assay Data for Compound A Stability Tablets Sample %LC Range (n-2, 5 tablet composite) 140 mg Tablet 95 0.2 .
105 mg Tablet 97 0.2 , 3 5mg Tablet 95 0.3 107161 Protocol (Blister Packaging) [0717] Tablets were Blister Packaged by Fisher = 5 tablets per strip (1 X 5), with 1 tab/ cavity = ALU/ALU ¨ blisters (Cold form foil) 107181 At each time point below, 5 strips (25 total tablets) were pulled at each time point for each stability condition for analysis.
Table 62: Blister Stability Conditions, Time Points and Testing Condition 1 Month (1) 3 Month (2) 6 Month (3) 12 Month (4) (a) 5 C. closed with desiccant A A A A
(b) 25 C/60% RH, closed with desiccant A A A A
(c) 40 C/75% RH, closed with desiccant A A : __ A
[0719] Stability study results are shown below in Tables 63-66.
Table 63: Summary of the 140 mg Dose Compound Tablet Bottle Stability Results 140mg, Formulation G2 Condition Initial 1 Month 3 Month 6 Month 25 C/60% RH Light Yellow Light Yellow Light Yellow Appearance Light Yellow ------------------------------------- 40 'C/754)/0 RH Light Yellow Ligiht Yellow Light Yellow _ 25 *C/60% RH 96 96 96 Assay 95 44) C175% RH 95 95 95 Total Related 25 C160% RH 0 28 0.35 0.24 0.36 .
Substances 40 'C/75% RH 0.33 0.27 0.55*
25 C/60% RH 3.64 3.71 3.90 Water Content 4.06 40 C/75% RH 3.70 4.57 5.06 25 C/60% RH 92 94 95 % LC at 45 minutes 95 .
40 cr/75% RH 93 93 92 25 C/60% RH 21.2 21.3 21.8 Tablet Hardness 21.8 40 (V/75% RH 21.8 21.0 19.4 *Increase appeats to be related to an inctease in peak at RRT4).43 Table 64: Summary of the 105 mg Dose Compound Tablet Bottle Stability Results 140mg, Formulation G2 Condition Initial I Month 3 Month 6 Month C Light Yellow Light Yellow Light Yellow Appearance 25 "C/60% RH Light Yellow Light Yellow Light Yellow Light Yellow 40 *C/75% RI'! Light Yellow Light Yellow Light Yellow Assay 25 'C/60% RH 97 99 98 100 . 40 *C/75% RI'! 97 98 97 . . .
5 C 0.31 0.24 .044 Total Related 25 C160% RH 0./5 0.34 0./5 0.47 Substances . 40 'C/75% RH 0.32 . 0.27 . 0.52* .
5 *C 3.04 2.78 3.11 Water Content 25 C160% RH 3.40 3./3 3.46 3.55 40 "C/75% RH 3.32 4.31 5.12 5 *C 92 95 95 % LC at 45 minutes 25 'C/60% RH 97 91 95 97 40 'C/75% RH 93 93 96 5 *C 19.9 20.4 18.2 Tablet Hardness 25 'C/60% RH 20.4 18.9 21,5 19,9 40 T175% RH 20.2 18.0 18.2 *Increase appeats to be telated to an increase in peak at RRT 0.43 Table 65: Summary of the 105 mg Dose Compound Tablet Blister Stability Results 140mg, Formulation G2 Condition initial I Month 3 Month 5 cl: Light Yellow . Light Yellow .
Appearance 25 C/60% Rif Light Yellow Light Yellow Light Yellow 40 C/75% RH Light Yellow Light Yellow . .
Assay 25 C/60% RH 97 99 99 40 C175% RH 99 97 5 C 0.46 . 0.44 .
Total Related 25 "C/60% Rif 0.25 0.46 0.45 Substances 40 'C/75% RH 0.41 0.39 5 C 3.55 3.56 Water Content 25 C/60% Rif , 3.4 3.56 3.61 40 C/75% RH 3.55 3.58 % IC at 45 minutes 25 'C/60% Rif , 97 97 95 40 'C/75% RH 95 94 5 C 20.4 18.1 Tablet Hardness 25 'C/60% RH 20.4 19.6 18.9 40 *C/75% RI'! ' 19.6 19.5 Table 66: Summary of the 35 mg Dose Compound Tablet Bottle Stability Results 140mg, Formulation G2 Condition Initial I Month 3 Month 6 Month 25 'C/60% RH Light Yellow Light Yellow Light Yellow Appearance Light 'Yellow 40 C175% RH Light Yellow Light Yellow Light Yellow 25 'C/60% Rif , 93 97 96 Assay 95 40 'C/75% RH 95 95 94 Total Related 25 'C/60% RH 0.35 0.19 0.47 Substances 40 'C/75% RH 0.26 0.32 0.27 0.50*
25 *C/60% RI'! 3.65 3.38 4.16 Water Content .5.05 40 C/75% RH 3.72 4.95 5.97 % IC at 45 minutes 25 'C/60% RH 94 91 94 94 40 C/75% RH 91 92 89 25 'C/60% RH 8.3 7.7 7.8 Tablet Hardness 8.0 C/75% R11 8.1 8.0 6.6 Increase appears to be related to an increase in peak at RRT 0.43 Embodiments:
107201 The aspects of the present disclosure are further described with reference to the following numbered embodiments:
1. A crystalline form of Compound A

NH

NC s./
C I ''''k's==()%µ. (Compound A) having a powder x-ray diffraction pattern comprising peaks at 7.6 0.2 20, 11.5 0.2' 20, and 17.6 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A.
2. The crystalline form of Compound A of Embodiment 1, further comprising a peak at 18.5' 71: 0.2 20.
3. The crystalline form of Compound A of Embodiment 1 or 2, further comprising a peak at 21.4 0.2 20.
4. The crystalline form of Compound A of any one of Embodiments 1-3, further comprising a peak at 3.1 0.2 20.
5. A crystalline form of Compound A having a powder x-ray diffraction pattern as shown in FIG. 3A.
6. A crystalline form of Compound A having a powder x-ray diffraction pattern comprising peaks at 11.0' 0.2 20, 16.1 0.2 20, and 17.9 0.20 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A.
7. The crystalline form of Compound A of Embodiment 6, further comprising a peak at 11.3 0.2 20.

8. The crystalline form of Compound A of Embodiment 6 or 7, further comprising a peak at 17.2 0.2 20.
9. The crystalline form of Compound A of any one of Embodiments 6-8, further comprising a peak at 7.9' 0.2 20.
10. A crystalline form of Compound A having a powder x-ray diffraction pattern as shown in FIG. 3C.
Ii. A process for manufacturing Compound A, wherein the process comprises the reductive amination of N-((1r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-l-yl)pytidazine-3-carboxamide (Intermediate 3) with 2-(2,6-dioxopiperidin-3-y1)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (Intermediate 5) and a reducing agent to provide Compound A:
N H2iti"Th 00 C"%--NH
Nr-Intermediate 3 intermediate 5 NLI
F' Compound A
=
12. The process of Embodiment 11, wherein the reductive amination is conducted in a polar solvent.
13. The process of Embodiment 12, wherein the polar solvent for the reductive amination is dimethylacetamide (DMA).

14. The process of any one of Embodiments 11-13, wherein the reducing agent for the reductive amination is sodium triacetoxyborohydride.
15. The process of any one of Embodiments 11-14, wherein the reductive amination is conducted at a temperature range of about -15 to about 30 C, about -10 to about 25 C, about -5 to about 20 C, about 0 to about 15 C, or about 5 to about 10 C.
16. The process of any one of Embodiments 11-15, wherein once the reductive amination reaction is complete, a mixture of ethanol and water is added to the crude reaction mixture to precipitate Compound A.
17. The process of Embodiment 16, wherein the mixture of ethanol to water has an ethanol :water ratio of about 1:1 (v/v).
18. The process of any one of Embodiments 11-17, wherein the reductive amination is conducted in the presence of a base 19. The process of Embodiment 18, wherein the base for the reductive amination is triethylamine or N-methyl morpholine.
20. The process of Embodiment 19, wherein the ratio of Intermediate 5 to base is about 1:0.7 (w/v).
21. The process of Embodiment 19, wherein the ratio of Intermediate 5 to base is about 1.7:1 (w/w).
22. The process of Embodiment 19, wherein the ratio of intermediate 5 to base is about 1.9:1 (w/w).
23. The process of any one of Embodiments 11-22, wherein the molar ratio of Intermediate 3 to Intermediate 5 is about 1.1:1.
24. The process of any one of Embodiments 11-22, wherein the molar ratio of Intermediate 3 to Intermediate 5 is about 1.05:1.
25. The process of any one of Embodiments 11-22, wherein the molar ratio of Intermediate 3 to Intermediate 5 is between about 1:1 and about 1.1:1.
26. The process of any one of Embodiments 11-22, wherein the molar ratio of Intermediate 3 to Intermediate 5 is about 1.0:1Ø

27. The process of any one of Embodiments 11-26, further comprising a step for the purification of Compound A.
28. The process of Embodiment 27, wherein the purification of Compound A.
comprises:
(Al) dissolving Compound A in about a mixture of dichloromethane and methanol;
(A2) filtering the solution comprising Compound A;
(A3) distillatively exchanging the solvent of the solution comprising Compound A with ethanol;
(A4) crystallizing Compound A from the ethanol solution; and (A5) drying the purified crystalline solid form of Compound A.
29. The process of Embodiment 28, wherein the ratio of dichloromethane to methanol in (Al) is about 9:1 (w/w).
30. The process of Embodiment 28, wherein the ratio of dichloromethane to methanol in (Al) is about 10:1 (v/v).
3 1 . The process of Embodiment 28, wherein the volume of ethanol in step (A3) is approximately 7 volumes relative to the amount of Intermediate 3 provided in the reductive amination step.
32. The process of Embodiment 31, wherein the amount of ethanol in step (A3) is corrected for the ethanol content in the crude Compound A.
33. The process of one of Embodiments 28-32, wherein the drying in step (A5) of the purified crystalline form of Compound A is conducted in vacuo.
34. The process of Embodiment 33, wherein the in vacuo drying occurs at about 15 to about 30 C, about 20 to about 30 C, about 30 to about 40 C, or about 35 to about 45 'C.
35. The process of Embodiment 33, wherein the in vacuo drying occurs at greater than about 50 C, greater than about 60 C, greater than about 70 C, or greater than about 80 C.

36. The process of Embodiment 33, wherein the in vacuo drying occurs at between about 60 C and about 70 C.
37 The process of Embodiment 33, wherein the in vacuo drying occurs at about 65 C.
38. The process of Embodiment 33, wherein the in vacuo drying occurs at between about 75 "C and about 85 'C.
39. The process of Embodiment 33, wherein the in vacuo drying occurs at about 80 C.
40. The process of any one of Embodiments 11-39, further comprising the oxidation of N-01r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)pi peri di n-1-yl)pyridazine-3-carboxamide (Intermediate 2) to form N-01r,40-4-(3-chloro-4-cyan ophenoxy)cy cl ohexyl)-6-(4-forrn yl pi peri din- I -yl)pyri dazi ne-3-carboxam i de (Intermediate 3):
N N
N
N
N
I
0' = 111 CI
Intermediate 2 Intermediate 3 41. The process of Embodiment 40, wherein the oxidation is performed using about 0.01 equivalents of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and about equivalents of sodium hypochlorite.
42. The process of Embodiment 40, wherein the oxidation is performed using about 0.01 equivalents of TEMPO and about 1.15 equivalent of sodium hypochlotite.
43. The process of any one of Embodiments 41 or 42, wherein the oxidation is performed in a solvent comprising dichloromethane.
44. The process of any one of Embodiments 41-43, wherein the oxidation occurs in the presence of a secondary alcohol.
45. The process of Embodiment 44, where in the secondary alcohol is isopropanol.

46. The process of any one of Embodiments 43-45, wherein the solvent for the oxidation further comprises aqueous sodium chloride.
47. The process of any one of Embodiments 40-46, wherein the oxidation is performed at a temperature less than about 25 C, less than about 20 C, less than about 15 C, less than about 10 C, less than about 5 C, less than about 0 C, less than about -5 "C, or less than about -11 C.
48. The process of any one of Embodiments 40-46, wherein the oxidation is performed at a temperature of about -11 C.
49. The process of any one of Embodiments 41-46, wherein the sodium hypochlorite is added over the course of less than 60 minutes, less than 45 minutes less than 30 minutes, or less than 20 minutes.
50. The process of any one of Embodiments 41-46, wherein the sodium hypochlorite is added over the course of between about 15 and about 45 minutes.
51. The process of any one of Embodiments 41-46, wherein the sodium hypochlorite is added over the course of about 30 minutes.
52. The process of any one of Embodiments 41-51, further comprising the step of exchanging the solvent comprising dichloromethane for a second solvent.
53. The process of Embodiment 52 wherein the second solvent comprises acetonitrile.
54. The process of Embodiment 52 wherein the second solvent comprises tetrahydrofuran.
55. The process of Embodiment 52, wherein the exchange of solvents is accomplished by distillation.
56. The process of any one of Embodiments 40-55 further comprising the step of purifying Intermediate 3 by recrystallization.
57. The process of Embodiment 56, wherein the purification of Intermediate 3 by recrystallization occurs in the presence of a solvent and an anti-solvent.
58. The process of Embodiment 56, wherein the recrystallization comprises the following steps:

Bi) combining crude Intermediate 3 with a mixture of solvent and anti-solvent;

Bii) stirring the mixture of crude Intermediate 3, solvent, and anti-solvent;
and Biii) filtering the mixture of crude Intermediate 3, solvent, and anti-solvent to obtain Intermediate 3.
59. The process of Embodiment 58, wherein the recrystallization solvent is a polar aprotic organic solvent and the anti-solvent is an aqueous solvent.
60. The process of Embodiment 59, wherein the recrystallization solvent for Intermediate 3 comprises acetonitrile.
61. The process of Embodiment 59, wherein the recrystallization solvent for In 3 comprises dichloromethane.
62. The process of Embodiment 59, wherein the recrystallization solvent for Intermediate 3 comprises tetrahydrofuran.
63. The process of Embodiment 59, wherein the recrystallization solvent for Intermediate 3 comprises dichloromethane and tetrahydrofuran.
64. The process of any one of Embodiments 59-63, wherein the recrystallization anti-solvent is water.
65. The process of any one of Embodiments 59-63, wherein the recrystallization anti-solvent comprises n-heptane.
66. The process of any one of Embodiments 59-65, wherein the ratio of recrystallization solvent to anti-solvent is about 1:1 (v/v).
67. The process of any one of Embodiments 59-65, wherein the ratio of recrystallization solvent to anti-solvent is about 1.04:1 (v/v).
68. The process of any one of Embodiments 59-65, wherein the ratio of recrystallization solvent to anti-solvent is about 0.6:1 (v/v).
69. The process of any one of Embodiments 59-68, wherein step Bii) is performed at a temperature between 15 C and 25 C.

70. The process of Embodiment 69, wherein step Bii) is performed at a temperature of about 18 'C.
71. The process of Embodiment 69, wherein step Bii) is performed at a temperature of about 20 C.
72. The process of any one of Embodiments 59-71, wherein the stirring of step Bii) is performed for at least 5 hours, at least 12 hours, at least 14 hours, at least 16 hours, or at least 18 hours.
73. The process of Embodiment 72, wherein the stirring of step Bii) is performed for at least 16 hours.
74. The process of Embodiment 72, wherein the stirring of step Bii) is performed for about 18 hours.
75. The process of any one of Embodiments 11-74, further comprising a nucleophilic aromatic substitution reaction of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (Intermediate 4) and piperidin-4-yl methanol in the presence of a base to provide N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yppyridazine-3-carboxamide (Intermediate 2):
CL N
N
N
Ha_OH
H
õ 10 ----ci N
intenmediate 4 intermediate 2 =
76. The process of Embodiment 75, wherein the nucleophilic aromatic substitution reaction is conducted in a polar solvent.
77. The process of Embodiment 76, wherein the polar solvent for the nucleophilic aromatic substitution is dimethylacetamide (DMA).
78. The process of any one of Embodiments 75-77, wherein the base for the nucleophilic aromatic substitution is N,N-diisopropylethylamine.

79. The process of any one of Embodiments 75-78, wherein the nucleophilic aromatic substitution reaction is conducted at a temperature of about 60 C to about 130 C, about 75 C to about 115 C, or about 90 C to about 100 C.
80. The process of any one of Embodiments 75-79, further comprising the step of purifying Intermediate 2 by recrystallization in an organic solvent.

81. The process of any one of Embodiments 75-80, wherein the recrystallization of Intermediate 2 further comprises the following steps:
Ci) combining crude Intermediate 2 in an organic solvent with an agent that promotes crystallization;
Cii) reducing the volume of organic solvent;
Ciii) adding additional amounts of the organic solvent;
Civ) stirring the mixture from part iii) at a temperature above 30 C;
Cv) cooling the mixture from part iii) to a temperature below 25 C;
Cvi) reducing the volume of organic solvent;
Cvii) stirring the mixture from part vi) at a temperature below 25 "C; and Cvii) filtering the mixture to obtain Intermediate 2.

82. The process of Embodiment 81, wherein the organic solvent in step Cii) is isopropyl acetate.

83. The process of Embodiment 81 or 82, wherein the agent that promotes crystallization in Ci) is a seed crystal of Intermediate 2.

84. The process of any one of Embodiments 81-83, wherein the reducing of the volume of organic solvent in step Ciii) is performed by vacuum distillation.

85. The process of any one of Embodiments 81-84, wherein the reducing of the volume of organic solvent in step Cvi) is performed by vacuum distillation.

86. The process of any one of Embodiments 81-85, wherein the temperature of step Civ) is about 50 C.

87. The process of any one of Embodiments 81-86, wherein the temperature of step Cv) is about 20 C.

88. The process of any one of Embodiments 81-87, wherein the temperature of step Cvii) is about 10 "C.

89. The process of any one of Embodiments 11-88, further comprising an amide coupling of 4-(((1.r,40-4-aminocyclohexypoxy)-2-chlorobenzonitrile hydrochloride (Intermediate 7) and 6-(4-(hydroxymethyppiperidin-1-yl)pyridazine-3-carboxylic acid (Intermediate 10), facilitated by a coupling agent, to provide N-01r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-y1)pyridazine-3-carboxamide (Intermediate 2):
N-N'ILOH
N
HC 1 *
Intermediate 10 Intermediate 7 N
CI
intermediate 2 =

90. The process of Embodiment 89, wherein the amide coupling is conducted in a polar solvent.

91. The process of Embodiment 90, wherein the polar solvent for the amide coupling is dimethylacetamide (DMA).

92. The process of any one of Embodiments 89-91, wherein the coupling agent for the amide coupling is a carbodiimide.

93. The process of Embodiment 92, wherein the carbodiimide is 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide.

94. The process of Embodiments 89-93, wherein the amide coupling reaction is conducted at a temperature of about 5 C to about 15 C, about 10 C to about 20 C, about 20 C to about 40 C, about 30 C to about 50 C, or about 35 C to about 45 C.

95. The process of any one of Embodiments 89-94, wherein the ratio of molar ratio of Intermediate 7 to Intermediate 10 is about 1.05:1.

96. The process of any one of Embodiments 89-94, wherein the ratio of molar ratio of Intermediate 7 to Intermediate 10 is about 1.02:1.

97. The process of any one of Embodiments 89-96, further comprising the step of purifying Intermediate 2 by recrystallization in an organic solvent.

98. The process of Embodiment 97, wherein the organic solvent for the recrystallization of Intermediate 2 is isopropyl acetate.

99. The process of Embodiment 97, wherein the organic solvent for the recrystallization of Intermediate 2 comprises tetrahydrofuran and n-heptane.

100. The process of any one of Embodiments 97-99, wherein the organic solvent for the recrystallization of Intermediate 2 is seeded with crystals of pure Intermediate 2.

101. The process of any one of Embodiments 97-100, wherein the recrystallization of Intermediate 2 is performed by reduction of the volume of the organic solvent for the recrystallization of Intermediate 2.

102. The process of Embodiment 101, wherein the reduction of the volume of the organic solvent for the recrystallization of Intermediate 2 is performed by vacuum distillation.

103. The process of any one of Embodiments 97-102 wherein the recrystallization of Intermediate 2 is performed by cooling the organic solvent for the recrystallization of Intermediate 2.

104. The process of Embodiment 103, wherein organic solvent for the recrystallization of Intermediate 2 is cooled to a temperature between about 15 C and about 25 C.

105. The process of Embodiment 103, wherein organic solvent for the recrystallization of Intermediate 2 is cooled to a temperature of about 20 C.

106. The process of any one of Embodiments 11-105, wherein the purified form of Compound A has a crystalline form with a powder x-ray diffraction pattern comprising peaks at 7.6 0.2" 20, 11..5 0.2 20, and 17.6 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A.

107. A compound which is:
6-chloro-N-01r,40-4-(3-chioro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide, CI N
I
intermediate 4

108. An ultrapure form of Compound A. having a purity greater than about 98%.

109. An ultrapure form of Compound A. having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 2:
N
=--'N
o Intermediate 2 =

110. The ultrapure form of Compound A of Embodiment 109, comprising less than about 0.5% of impurity Intermediate 2.

111. The ultrapure form of Compound A of Embodiment 109, comprising less than about 0.2% of impurity Intermediate 2.

112. An ultrapure form of Compound A. having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 3:

_N N
---- jNil Intermediate 3 =

113. The ultrapure form of Compound A of Embodiment 112, comprising less than about 0.5% of impurity Intermediate 3.

114. The ultrapure form of Compound A of Embodiment 112, comprising less than about 0.1% of impurity Intermediate 3.

115. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 5:
H21t1"-io 0 ci NH
Intermediate 5

116. The ultrapure form of Compound A of Embodiment 115, comprising less than about 0.5% of impurity Intermediate 5.

117. The ultrapure form of Compound A of Embodiment 115, comprising less than about 0.1 % of impurity Intermediate 5.

118. The ultrapure form of Compound A of Embodiment 115, comprising less than about 0.05% of impurity intermediate 5.

119. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of Impurity 1:

OH
N N
'N
H
N N
11.1 CI
Impurity 1 =

120. The ultrapure form of Compound A of Embodiment 119, comprising less than about 0.5% of Impurity 1.

121. The ultrapure form of Compound A of Embodiment 119, comprising less than about 0.1% of Impurity 1.

122. The ultrapure form of Compound A. of Embodiment 119, comprising than about 0.05 /0 of Impurity 1.

123. An ultrapure form of Compound A haying a purity greater than about 95%, and comprising less than about 1% of Impurity 2:
r e,Js 0 '"'Nisi^
1.4 ==7" "=-===
NO re-syr:i f_\. rs¨

e'r L.). C.
Impurity 2.

124. The ultrapure form of Compound A of Embodiment 123, comprising less than about 0.5% of Impurity 2.

125. The ultrapure form of Compound A. of Embodiment 123, comprising less than about 0.2% of Impurity 2.

126. The ultrapure form of Compound A of Embodiment 123, comprising less than about 0.15% of Impurity 2,

127. An ultrapure form of Compound A having a purity greater than about 95%, and comprising less than about 1% of Impurity 3:

1 c I. ts1 ks.
(---`e(s I-14\ -r -"' , Impurity 3.

128. The ultrapure form of Compound A of Embodiment 127, comprising less than about 0.5% of Impurity 3.

129. The ultrapure form of Compound A of Embodiment 128, comprising less than about 0.2% of Impurity 3.

130. The ultrapure form of Compound A of Embodiment 129, comprising less than about 0.15% of Impurity 3.

131. An ultrapure form of Compound A having a purity greater than about 95%, and comprising less than about 1% of Impurity 4:

f. ) 6 NC N

0 0 Ale a C.}
Impurity 4.
1.32. The ultrapure form of Compound A of Claim 131., comprising less than about 0.5% of Impurity 4.
133. The ultrapure form of Compound A of Embodiment 131, comprising less than about 0.2% of Impurity 4.
134. The ultrapure form of Compound A of Embodiment 131, comprising less than about 0.15% of Impurity 4.
1.35A. The ultrapure form of Compound A of any one of Embodiments 108-134, wherein the purity of Compound A is determined by HPLC.

135B. The ultrapure form of Compound A of any one of Embodiments 109-1.35A, wherein the amount of the Intermediate or Impurity is determined by HPLC.
136. The ultrapure form of Compound A. of any one of Embodiments 108-135A., wherein the purity of Compound A is greater than about 99%, about 99.5%, or about 99.9%.
137. The ultrapure form of Compound A of any one of Embodiments 108-135, wherein the purity of Compound A is greater than about 99.5%.
138. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of at least two of the following impurities:
Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
139. The ultrapure form of Compound A of embodiment 138, wherein the purity of Compound A. is greater than about 99%.
140. The ultrapure form of Compound A of any one of Embodiments 108-135, comprising less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, or about 0.5% of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.
141. The ultrapure form of Compound A of any one of Embodiments 108-135, wherein the Compound A has a purity of about 99.9%.
142. The ultrapure form of Compound A of any one of Embodiments 108-141, wherein Compound A. is in amorphous form.
143. The ultrapure form of Compound A. of any one of Embodiments 108-141, characterized by a glass transition temperature, Tg, of 146 C at 25 C and 0%
relative humidity.
144. The ultrapure form of Compound A of any one of Embodiments 108-141, further characterized by a glass transition temperature, Tg, of 103 C at 40 C and 75%
relative humidity.
145. The ultrapure form of Compound A of any one of Embodiments 108-144, further characterized by a Dv(50) particle size of about 5 to about 20 gm.

146. The ultrapure form of Compound A of any one of Embodiments 108-145, further characterized by a Dv(50) particle size of about 5 to about 15 pm.
147. The ultrapure form of Compound A. of any one of Embodiments 108-146, characterized by a Dv(50) particle size of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 pm.
148. The ultrapure form of Compound A of any one of Embodiments 145-147, wherein particle size is measured by laser diffraction.
149. The ultrapure form of Compound A according to any one of Embodiments 108-148, characterized in that the amorphous form is stable for at least 1 month at 2-8 C; for at least 1 month at 25 C and 60% relative humidity; and for at least 1 month at 40 C and 75%
relative humidity.
150. A process for manufacturing the amorphous form of Compound A of any one of Embodiments 108-149, wherein the process comprises the following steps:
(D1) dissolving crystalline Compound A in solvent to afford a solution of Compound A;
(D2) introducing the Compound A solution from step (1) into a spray dryer;
(D3) spraying the Compound A solution from the spray dryer to form the amorphous form of the Compound A;
and (D4) Removing the residual solvent from the amorphous form of Compound A.
151. The process of Embodiment 150, wherein, the solvent of step (D1) is a mixture of di chlorom ethane and methanol.
152. The process of Embodiment 151, wherein the solvent of step (D1) is a mixture of about 95:5 (w/w) to about 80:20 (w/w) dichloromethane:methanol.
153. The process of any one of Embodiments 150-152, wherein the solvent of step (D1) is about a 90:10 (w/w) mixture of dichloromethane:methanol.
154. The process of any one of Embodiments 150-152, wherein the solvent of step (D1) is about a 95:5 (w/w) mixture of dichloromethane:methanol.

155. The process of any one of Embodiments 150-152, wherein the solvent of step (D1) is about a 93:7 (w/w) mixture of dichloromethane:methanol.
156. The process of any one of Embodiments 1.50-152, wherein removal of residual solvent in step (D4) is accomplished by tray-drying.
157. The process of any one of Embodiments 150-156, wherein removal of residual solvent in step (1)4) is accomplished by filter-drying.
158. The process of any one of Embodiments 150-156, wherein the removal of residual solvent in step (D4) is accomplished by tumble drying.
159. The process of any one of Embodiments 150-156, wherein the removal of residual solvent in step (D4) is accomplished by agitated conical drying.
160. The process of any one of Embodiments 150-156, wherein the removal of residual solvent in step (D4) is accomplished by fluid bed drying.
161. An oral dosage form comprising one or more pharmaceutically acceptable excipients and Compound A of any one of Embodiments 108-160, wherein the oral dosage form is selected from the group consisting of a tablet, a sachet, or a capsule.
162. The oral dosage form of Embodiment 161, wherein the Compound A is the ultrapure form of Compound A of any one of Embodiments 108-149.
163. The oral dosage form of Embodiment 161 or 162, wherein the oral dosage form is a tablet.
164. The oral dosage form of Embodiment 161 or 162, wherein the oral dosage form is a sachet.
165. The oral dosage form of Embodiment 161 or 162, wherein the oral dosage form is a capsule.
166. The tablet of Embodiment 163, wherein the amount of Compound A in the tablet is between about 5 mg and 1000 mg.
167. The tablet of Embodiment 166, wherein the amount of Compound A in the tablet is about 35 mg to about 280 mg.

168. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 35 mg.
169. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 70 mg .
170. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 105 mg.
171. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 140 mg.
172. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 175 mg 173. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 210 mg.
174. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 245 mg.
175. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 280 mg.
176. The tablet of any one of Embodiments 163 or 166-175, wherein the pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, and lubricants.
177. The tablet of Embodiment 176, wherein the filler is microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, fast-dissolving carbohydrates such as PharmaburstTM, or any mixture thereof.
178. The tablet of Embodiment 176, wherein the di sintegrant is sodium starch glycol ate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmel lose sodium, crospovidone, chitosan, agar, alginic acid, calcium alginate, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkyl substituted hydroxypropyl cellulose, hydroxylpropyl starch, low-substituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, magnesium aluminum silicate, polacrilin potassium, povidone, or any mixture thereof.
179. The tablet of Embodiment 176, wherein the glidant is silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, or any mixture thereof.
180. The tablet of Embodiment 176, wherein the lubricant is magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, light mineral oil, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, or any mixture thereof.
181. The tablet of any one of Embodiments 163 or 166-175, comprising:
About 1 to about 50% w/w of Compound A;
About 35 to about 60% w/w microcrystalline cellulose;
About 15 to about 50% w/w lactose monohydrate;
About 1 to about 5% w/w croscarrnellose sodium;
0 to about 1 % w/w silicon dioxide; and 0 to about 1 % w/w magnesium stearate.
182. The tablet of any one of Embodiments 163 or 166-175, comprising:
About 5 % w/w of Compound A;
About 45.5 % w/w microcrystalline cellulose;
About 45.5 % w/w lactose monohydrate;
About 3 w/w croscarmellose sodium;
About 0.5 % w/w silicon dioxide; and About 0.5 % w/w magnesium stearate.
183. The tablet of any one of Embodiments 163 or 166-175, comprising an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises About 10 to about 40% w/w of Compound A;
About 35 to about 60% w/w microcrystalline cellulose;
About 15 to about 30% w/w lactose monohydrate;

About 1 to about 10% w/w croscarmellose sodium;
0 to about 1 % w/w silicon dioxide; and 0 to about 0.5% w/w magnesium stearate;
and wherein the extra-granular portion comprises About 1 to about 5% w/w croscarmellose sodium;
0 to about 1 % w/w magnesium stearate; and 0 to about 2 % w/w silicon dioxide.
184. The tablet of any one of Embodiments 163 or 166-175, comprising an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:
About 20% w/w of Compound A;
About 48.7% w/w microcrystalline cellulose;
About 24.3% w/w lactose monohydrate;
About 3% w/w croscarmellose sodium;
About 0.5 % w/w silicon dioxide; and About 0.25% w/w magnesium stearate;
and wherein the extra-granular portion comprises:
About 2% w/w croscarmellose sodium;
About 0.5% w/w magnesium stearate; and About 0.25 % w/w silicon dioxide.
185. The tablet of Embodiment 183 or 184, wherein the silicon dioxide in the extra-granular portion comprises fumed silica.
186. The tablet of any one of Embodiments 183-1.85, wherein the silicon dioxide in the extra-granular portion comprises fumed silica after treated with dimethyldichlorosilane.
187. The tablet of any one of Embodiments 183-186, wherein the silicon dioxide in the extra-granular portion comprises fumed silica chemically modified with trimethylsilyl groups on the surface of the silica.
188. The tablet of any one of Embodiments 163 or 166-187, wherein the Compound A
is an ultrapure form of Compound A.

189. The tablet of any one of Embodiments 163 or 166-187, wherein the Compound A
is prepared according to the process of any one of Embodiments 150-160.
190. A method of manufacturing the tablet of any one of Embodiments 163 or 166-comprising the following steps:
(El) blending a form of Compound A with at least one pharmaceutically acceptable excipient to create a powder;
(E2) delumping the powder from step (El), adding at least one pharmaceutically acceptable excipient, and blending to create a first blend;
(E3) granulating the blend from step (E2) and passing the resultant powder through a screen to produce a plurality of granules;
(E4) adding at least one pharmaceutically acceptable excipient to plurality of granules from step (E3) and blending to produce a second blend; and (ES) compressing the second blend from step (E4) into one or more tablets.
191. The method of Embodiment 190, wherein the form of Compound A in step (El) is the amorphous form of Compound A.
192. The method of Embodiment 190 or 191, wherein, in step (El), Compound A is blended with at least one filler, at least one disintegrant, and at least one glidant.
193. The method of Embodiment 192, wherein, in step (El), Compound A is blended with two fillers, one disintegrant, and one glidant.
194. The method of Embodiment 192, wherein, in step (El), Compound A is blended with two fillers, one disintegrant, one glidant, and one lubricant.
195. The method of Embodiment 193 or 194, wherein at least one filler is mi crocry stal 1 i ne cellulose.
196. The method of Embodiments 193-195, wherein at least one filler is lactose monohydrate.
197. The method of any one of Embodiments 190-196, wherein at least one disintegrant is croscarrnellose sodium.

198. The method of any one of Embodiments 190-197, wherein at least one glidant is silicon dioxide.
199. The method of any one of Embodiments 190-198, wherein a least one lubricant is magnesium stearate.
200. The method of any one of Embodiments 190-199, wherein at least one pharmaceutically acceptable excipient of step (E2) is a lubricant.
201. The method of Embodiment 200, wherein at least one lubricant is magnesium stearate.
202. The method of any one of Embodiments 190-201, wherein the at least one pharmaceutically acceptable excipient of step (E4) comprises at least one lubricant.
203. The method of Embodiment 202, wherein the at least one lubricant is extragranular magnesium stearate.
204. The method of any one of Embodiments 190-203, wherein at least one glidant, at least one disintegrant, and at least one lubricant are added to the plurality of granules in step (FA).
205. The method of Embodiment 204, wherein at least one glidant added in step (FA) is silicon dioxide.
206. The method of any one of Embodiment 204 or 205, wherein at least one di sintegrant added in step (E4) is croscarmellose sodium.
207. The method of any one of Embodiments 204-206, wherein at least one lubricant added in step (4) is magnesium stearate.
208. The method of any one of Embodiments 190-207, wherein the blend from step (E4) is compressed in step (ES) using a rotary press.
209. A method of treating cancer in a subject comprising administering to a subject in need of said treatment one or oral dosage forms of any one of Embodiments 161-189.
210. The method of Embodiment 209, wherein the cancer is prostate cancer.

211. The method of Embodiment 210, wherein the prostate cancer is metastatic castration resistant prostate cancer.
21.2. The method of any one of Embodiments 209-211, wherein the one or more tablets are administered to the subject once a day, twice a day, three times a day, or four times a day.
213. The method of any one of Embodiments 209-212, wherein the one or more tablets are administered to the subject all at once or subdivided in two, three, four, or more sub-portions.
214. The method of any one of Embodiments 209-213, wherein the subject is in a fed state.
215. The method of any one of Embodiments 209-213, wherein the subject is in a fasted state.
216. The method of any one of Embodiments 209-215, wherein the subject is also taking or being administered an antacid medication.
217. The method of any one of Embodiments 209-216, further comprising administering an additional anti-cancer agent.
218. The method of Embodiment 217, wherein the additional anti-cancer agent is a PARP inhibitor.

Claims (91)

PCT/US2021/031091

1. A crystalline form of Compound A
having a powder x-ray diffraction pattern comprising peaks at 7.6 0.2' 20, 11.5" 0.2 20, and 17.6 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A.

2. The crystalline form of Compound A of claim 1, further comprising a peak at 18.5 0.2" 20.

3. The crystalline form of Compound A of claim 1 or 2, further comprising a peak at 21.4 0.2 20.

4. The crystalline form of Compound A of any one of claims 1-3, further comprising a peak at 3.1 0.2 20.

5. A crystalline form of Compound A having a powder x-ray diffraction pattern as shown in FIG. 3A.

6. A crystalline form of Compound A having a powder x-ray diffraction pattern comprising peaks at 11.0" 0.2" 20, 16.1 0.2" 20, and 17.9 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A.

7. The crystalline form of Compound A of claim 6, further comprising a peak at 11.3 0.2" 20.

8. The crystalline form of Compound A of claim 6 or 7, further comprising a peak at 17.2 0.2 20.

9. The crystalline form of Compound A of any one of claims 6-8, further comprising a peak at 7.90 0.2 20.

10. A crystalline form of Compound A having a powder x-ray diffraction pattern as shown in FIG. 3C.

11.. A process for manufacturing Compound A, wherein the process comprises the reductive am i nati on of N-((1r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin- 1 -yl)pyridazine-3-carboxamide (Intermediate 3) with 242,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (Intermediate 5) and a reducing agent to provide Cornpound A:

12. The process of claim 11, further comprising a step for the purification of Compound A.

13. The process of claim 1.2, wherein the purification of Compound A
comprises:
(A1) dissolving Compound A in about a mixture of dichlorornethane and methanol;
(A2) filtering the solution comprising Compound A;
(A3) distillatively exchanging the solvent of the solution comprising Compound A with ethanol;
(A4) crystallizing Compound A from the ethanol solution; and (A5) drying the purified crystalline solid form of Compound A.

14. The process of any one of claims 11-13, further comprising the oxidation of N-((1r,40-4-(3-chl oro-4-cy anoph enoxy)cycl oh exyl)-6-(4-(hy droxym ethyl)pi peri din- I -yl)pyridazine-3-carboxamide (Intermediate 2) to form N-((lr,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (Intermediate 3):

15. The process of claim 14 further comprising the step of purifying Intermediate 3 by recrystallization.

16. The process of any one of claims 11-15, further comprising a nucleophilic aromatic substitution reaction of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cycl ohexyl)pyri dazine-3-carboxami de (Intermediate 4) and pi peri d n-4-yi methanol in the presence of a base to provide N-41r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-l-y1)pyridazine-3-carboxamide (Intermediate 2):

17. The process of claim 16, further comprising the step of purifying intermediate 2 by recrystallization in an organic solvent.

18. The process of any one of claims 11-17, further comprising an amide coupling of 44(1r,40-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (Intermediate 7) and 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (Intermediate 10), facilitated by a coupling agent, to provide N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-y1)pyridazine-3-carboxamide (Intermediate 2):

19. The process of claim 18, further comprising the step of purifying Intermediate 2 by reaystallization in an organic solvent.

20. The process of any one of claims 11-19, wherein the purified form of Compound A has a crystalline form with a powder x-ray diffraction pattern comprising peaks at 7.6 0.2 20, 11.5' 0.2 20, and 17.6 0.2 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 A.

21. A compound which is:
6-chloro-N-01r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxarnide,

22. An ultrapure form of Compound A having a purity greater than about 98%.

23. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 2:

24. The ultrapure form of Compound A of claim 23, comprising less than about 0.5%
of impurity Intermediate 2.

25. An ultrapure form of Cornpound A having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 3:

26. The uitrapure form of Compound A. of claim 25, comprising less than about 0.5%
of impurity Intermediate 3.

27. An ultrapure form of Compound A haying a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 5:

28. The ultrapure form of Compound A of claim 27, comprising less than about 0.5%
of impurity Intermediate 5.

29. An ultrapure form of Cornpound A having a purity greater than about 98%, and comprising less than about 1% of Impurity 1:

30. The ultrapure forrn of Compound A of claim 29, comprising less than about 0.5%
of Impurity I.

3 1 . An ultrapure form of Compound A having a purity greater than about 95%, and comprising less than about 1% of Impurity 2:
<DIG>

32. The ultrapure form of Compound A. of claim 31, comprising less than about 0.5%
of Impurity 2.

33. An ultrapure form of Compound A haying a purity greater than about 95%, and comprising less than about 1% of Impurity 3:

34. The ultrapure form of Compound A of claim 33, comprising less than about 0.5%
of Impurity 3.

35. An ultrapure form of Compound A having a purity greater than about 95%, and comprising less than about 1% of Impurity 4:

36. The ultrapure form of Compound A of claim 35, comprising less than about 0.5%
of 1 na purity 4.

37. The ultrapure form of Compound A of any one of claims 22-36, wherein the purity of Compound A is determined by HPLC.

38. The ultrapure form of Compound A of any one of claims 23-37, wherein the amount of the Intermediate or Impurity is determined by HPLC.

39. The ultrapure form of Compound A of any one of claims 22-38, wherein the purity of Compound A is greater than about 99%, about 99.5%, or about 99.9%.

40. The ultrapure form of Compound A of any one of claims 22-38, wherein the purity of Compound A is greater than about 99.5%.

41. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of at least two of the following impurities:
Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

42. The ultrapure form of Compound A of claim 41, wherein the purity of Compound A is greater than about 99%.

43. The ultrapure form of Compound A of any one of claims 22-38, comprising less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, or about 0.5% of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

44. The ultrapure form of Compound A of any one of claims 22-38, wherein the Compound A has a purity of about 99.9%.

45. The ultrapure form of Compound A of any one of claims 22-44, wherein Compound A is in amorphous form.

46. The ultrapure form of Compound A. of any one of claims 22-45, further characterized by a Dv(50) particle size of about 5 to about 20 pm.

47. A process for manufacturing the amorphous form of Compound A of any one of claims 22-46, wherein the process comprises the following steps:
(D1) dissolving crystalline Compound A in solvent to afford a solution of Compound A;
(D2) introducing the Compound A solution from step (1) into a spray dryer;
(D3) spraying the Compound A solution from the spray dryer to form the amorphous form of the Compound A; and (D4) Removing the residual solvent from the amorphous form of Compound A.

48. The process of claim 47, wherein, the solvent of step (D1) is a mixture of dichloromethane and methanol.

49. The process of claim 48, wherein the solvent of step (D1) is a mixture of about 95:5 (w/w) to about 80:20 (w/w) dichloromethane:methanol.

50. An oral dosage form comprising one or more pharmaceutically acceptable excipients and Compound A of any one of claims 22-46, wherein the oral dosage form is selected from the group consisting of a tablet, a sachet, or a capsule.

51. The oral dosage form of claim 50, wherein the Compound A is the ultrapure form of Compound A of any one of claims 22-46.

52. The oral dosage form of claim 50 or 51, wherein the oral dosage form is a tablet.

53. The tablet of claim 52, wherein the amount of Compound A. in the tablet is between about 5 mg and 1000 mg.

54. The tablet of claim 53, wherein the amount of Compound A in the tablet is about 35 mg to about 280 mg.

55. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 35 mg.

56. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 70 mg .

57. The tablet of claim 54, wherein the amount of Compound A. in the tablet is about 105 mg.

58. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 140 mg.

59. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 175 mg.

60. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 210 mg.

61. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 245 mg.

62. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 280 mg.

63. The tablet of any one of claims 52-62, wherein the pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, and lubricants.

64. The tablet of claim 63, wherein the filler is microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, fast-dissolving carbohydrates such as PharmaburstTM, or any mixture thereof.

65. The tablet of claim 63, wherein the di sintegrant is sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, chitosan, agar, alginic acid, calcium alginate, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkylsubstituted hydroxypropyl cellulose, hydroxylpropyl starch, low-substituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, magnesium aluminum silicate, polacrilin potassium, povidone, or any mixture thereof.

66. The tablet of claim 63, wherein the glidant is silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, or any mixture thereof.

67. The tablet of claim 63, wherein the lubricant is magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, light mineral oil, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, or any mixture thereof.

68. The tablet of any one of claims 52-62, comprising:
About 1 to about 50% w/w of Compound A;
About 35 to about 60% w/w microcrystalline cellulose;
About 15 to about 50% w/w lactose monohydrate;
About 1 to about 5% w/w croscarmellose sodium;
0 to about 1 % w/w silicon dioxide; and 0 to about 1 % w/w magnesium stearate.

69. The tablet of any one of claims 52-62, comprising:
About 5 w/w of Compound A;
About 45.5 % w/w microcrystalline cellulose;
About 45.5 % w/w lactose monohydrate;
A.bout 3 % w/w croscarmellose sodium;
About 0.5 % w/w silicon dioxide; and About 0.5 % w/w magnesium stearate.

70. The tablet of any one of claims 52-62, comprising an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises About 10 to about 40% w/w of Compound A;
A.bout 35 to about 60% w/w microcrystalline cellulose;
About 15 to about 30% w/w lactose monohydrate;
About 1 to about 10% w/w croscarmellose sodium;
0 to about 1 % w/w silicon dioxide; and 0 to about 0.5% w/w magnesium stearate;

and wherein the extra-granular portion cornprises About 1 to about 5% w/w croscarmellose sodium;
0 to about 1 % w/w m.agnesium. stearate; and 0 to about 2 % w/w silicon dioxide.

71. The tablet of any one of claims 52-62, comprising an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:
About 20% w/w of Compound A;
About 48.7% w/w microcrystalline cellulose;
About 24.3% w/w lactose monohydrate;
About 3% w/w croscarmellose sodium;
About 0.5 % w/w silicon dioxide; and About 0.25% w/w magnesium stearate;
and wherein the extra-granular portion comprises:
About 2% w/w croscarmellose sodium;
About 0.5% w/w magnesium stearate; and About 0.25 % w/w silicon dioxide.

72. The tablet of any one of claims 52-71, wherein the Compound A is an ultrapure fonn of Compound A.

73. The tablet of any one of claims 52-71, wherein the Com.pound A. is prepared according to the process of any one of claims 47-49.

74. A method of manufacturing the tablet of any one of claims 52-71 comprising the following steps:
(El) blending a form of Compound A. with at least one pharmaceutically acceptable excipient to create a powder;
(E2) delumping the powder from step (El), adding at least one pharmaceutically acceptable excipient, and blending to create a first blend;
(E3) granulating the blend from step (E2) and passing the resultant powder through a screen to produce a plurality of granules;

(E4) adding at least one pharmaceutically acceptable excipient to plurality of granules from step (E3) and blending to produce a second blend; and (E5) compressing the second blend frorn step (E4) into one or m.ore tablets.

75. The method of claim 74, wherein the form of Compound A in step (El) is the amorphous form of Compound A.

76. The method of claim 74 or 75, wherein, in step (El), Cornpound A is blended with at least one filler, at least one disintegrant, and at least one glidant.

77. The method of claim 76, wherein, in step (E1), Cornpound A is blended with two fillers, one disintegrant, and one glidant.

78. The method of claim. 76, wherein, in step (E1), Compound A is blended with two fillers, one disintegrant, one glidant, and one lubricant.

79. The method of any one of claims 74-78, wherein at least one pharmaceutically acceptable excipient of step (E2) i.s a lubricant.

80. The method of any one of claims 74-79, wherein the at least one pharmaceutically acceptable excipient of step (E4) comprises at least one lubricant.

81. The method of any one of claims 74-80, wherein at least one glidant, at least one disintegrant, and at least one lubricant are added to the plurality of granules in step (E4).

82. A method of treating cancer in a subject comprising administering to a subject in need of said treatrnent one or oral dosage forms of any one of claims 50-73.

83. The method of claim 82, wherein the cancer is prostate cancer.

84. The inethod of claim 83, wherein the prostate cancer is metastatic castration resistant prostate cancer.

85. The method of an.y one of claims 82-84, wherein the one or m.ore tablets are administered to the subject once a day, twice a day, three times a day, or four times a day.

86. The method of any one of claims 82-85, wherein the one or more tablets are adrninistered to the subject all at once or subdivided in two, three, four, or rnore sub-portions.

87. The rnethod of any one of clairns 82-86, wherein the subject is in a fed state.

88. The method of any one of claims 82-86, wherein the subject is in a fasted state.

89. The method of any one of claims 82-88, wherein the subject is also taking or being admi ni stered an antacid medi cati on.

90 The rnethod of any one of claims 82-89, further comprising administering an additional anti-cancer agent.

91. The method of claim 90, wherein the additional anti-cancer agent is a PARP
inhibitor.